Pyrimido-pyridazinone compounds and methods of use thereof

ABSTRACT

The present application provides novel pyrimido-pyridazinone compounds and methods for preparing and using these compounds. These compounds are useful in treating inflammation in patients by administering one or more of the compounds to a patient. In one embodiment, the novel pyrimido-pyridazinone compound is of Formula (I) and R 1  and R 2  are defined herein.

BACKGROUND

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within cells. Almost all kinases contain asimilar 250 to 300 amino acid catalytic domain. The kinases can becategorized into families by the substrates they phosphorylate.

JAK2 (Janus kinase 2) is a family of intracellular non-receptor tyrosinekinases. JAK2 is expressed ubiquitously in hematopoietic cells andabundantly in primary leukemic cells from children with acutelymphoblastic leukemia. The downstream substrates of JAK include thesignal tranducer activator of transcription (STAT) proteins. STATproteins function both as signaling molecules and transcription factorsand ultimately bind to specific DNA sequences present in the promotersof cytokine-responsive genes. JAK/STAT signaling has been implicated inthe mediation of many abnormal immune responses such as allergies,asthma, autoimmune diseases such as transplant (allograft) rejection,rheumatoid arthritis, amyotrophic lateral sclerosis and multiplesclerosis, as well as in solid and hematologic malignancies such asleukemia and lymphomas.

Spleen tyrosine kinase (syk) is a member of the syk family of proteintyrosine kinases and plays a crucial role in inflammatory and allergicresponses. Syk triggers IgE and IgG receptor mediated signaling in mastcells, basophils, and macrophages leading to degranulation and cytokinerelease.

Immunoreceptor tyrosine activation motif (ITAM)-mediated signaling hasemerged as a primary event in signaling pathways responsible for humanpathologies. ITAM-mediated signaling is responsible for relayingactivation signals initiated at classical immune receptors such asT-cell receptors, B-cell receptors, and Fc receptors in immune cells andat GPVI and FcγRIIa in platelets to downstream intracellular moleculessuch as Syk.

The binding of a ligand to an ITAM-containing receptor triggerssignaling events which allows for the recruitment of proteins from afamily of nonreceptor tyrosine kinases called the Src family. Thesekinases phosphorylate tyrosine residues within the ITAM sequence, aregion with which the tandem SH2 domains on either Syk or ZAP-70interact. The interaction of Syk with diphosphorylated ITAM sequencesinduces a conformation change in the kinases that allows for tyrosinephosphorylation of the kinase itself.

Not only do these kinases contribute to normal host defense, they alsoplay roles in the pathogenesis of diseases. Many diseases are associatedwith abnormal cellular responses triggered by protein kinase-mediatedevents. These diseases include autoimmune diseases, inflammatorydiseases, bone diseases, metabolic diseases, neurological andneurodegenerative diseases, cancer, cardiovascular diseases, allergies,asthma, Alzheimer's disease and hormone-related diseases. As aconsequence, there have been substantial efforts in medicinal chemistryto find inhibitors of protein kinases for use as therapeutic agents.

There is a need in the art for compounds that are dual inhibitors ofSyk/JAK2, as well as for methods for treating conditions that canbenefit from such inhibition.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of Formula (I),wherein R¹ and R² are defined herein.

In another aspect, the invention provides a pharmaceutical compositioncontaining a compound of Formula (I) and a pharmaceutically acceptablecarrier.

In a further aspect, the invention provides a method for co-regulatingJAK-2 and Syk by administering a therapeutically effective amount of acompound of Formula (I) to a patient in need thereof.

In yet another aspect, methods for treating inflammation are providedand include administering a compound of Formula (I) to a patient in needthereof.

Other aspects and advantages of the invention will be readily apparentfrom the following detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A, 1B, 2A and 2B provide comparative data illustrating theanti-inflammatory effects of methotrexate, a known anti-inflammatory,and a compound described herein which is encompassed by the compound ofFormula (I), using the Collagen Induced Arthritis (CIA) model of humanrheumatoid arthritis (RA) in female lewis rats. After type II collagen(cII) induced CIA, the compound of Example 19 (2×30 mg/kg) andmethotrexate (0.5 mg/kg) were administered daily or twice daily,respectively, to separate rats.

FIG. 1A illustrates anti-inflammatory effects as a function of theamount of edema (mL) vs. time (days). The black diamonds (♦) representresults for the control. The triangles (▴) represent results for thecompound of Example 19. The crosses (x) represent results formethotrexate.

FIG. 1B illustrates anti-inflammatory effects as a function of theamount of edema (mL) vs. time (days). The circles (●) represent resultsfor the control. The inverted triangles (▾) represent results for thecompound of Example 62. The astericks (*) represent results for thecompound of Example 108. The squares (▪) represent results for thecompound of Example 189. The diamonds (♦) represent results for thecompound of Example 191.

FIG. 2A illustrates anti-inflammatory effects as a function of arhtriticscore (per rat) vs. time (days). The black diamonds (♦) representresults for the control. The triangles (▴) represent results for thecompound of Example 19. The crosses (x) represent results formethotrexate.

FIG. 2B illustrates anti-inflammatory effects as a function of arhtriticscore (per rat) vs. time (days). The circles (●) represent results forthe control. The triangles (▴) represent results for the compound ofExample 62. The astericks (*) represent results for the compound ofExample 108. The squares (▪) represent results for the compound ofExample 189. The diamonds (♦) represent results for the compound ofExample 191.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides compounds and pharmaceutical composition thereof,which are capable of reducing or eliminating inflammation caused bytissue insult, injury, or pathology. The invention further providescompounds and compositions which function through a protein kinaseinhibitory mechanism.

In one aspect, the present invention provides a compound of Formula (I):

In this formula, R¹ is NR⁴R⁵, optionally substituted C₁ to C₆ alkoxy,optionally substituted C₆ to C₁₄ aryl, optionally substitutedheteroaryl, optionally substituted 3-10 membered monocyclic or bicycliccycloalkyl, or optionally substituted 3-10 membered monocyclic orbicyclic heterocyclyl. In one aspect, the 3-4 membered cycloalkyl andheterocyclyl are saturated. In another aspect, the hydrogen atoms on thesame carbon atom of the cycloalkyl or heterocyclyl are optionallyreplaced with an optionally substituted 3-6 membered cycloalkyl orheterocyclyl to form a spirocycloalkyl or spiroheterocyclyl. In afurther aspect, the hydrogen atoms on the same atom of the cycloalkyl orheterocyclyl are optionally replaced with O to form an oxo substituent.

-   -   i. In another embodiment, R¹ is N(C₁ to C₆ alkyl)(C₁ to C₆        alkyl) or C₁ to C₆ alkoxy.    -   ii. In still a further embodiment, R¹ is N(CH(CH₃)₂)₂, N(CH₃)₂,        OCH₂CH₃, or OCH₃.    -   iii. In another embodiment, R¹ is optionally substituted phenyl.    -   iv. In still another embodiment, R¹ is of the structure:

-   -    wherein, R²², R²³, R²⁴, R²⁵, and R²⁶ are, independently, H,        C(O)(C₁ to C₆ alkoxy), C(O)OH, O(C₁ to C₃ perfluoroalkyl), O(C₁        to C₆ perfluoroalkoxy), C₁ to C₆ alkoxy, halogen, (C₁ to C₆        alkyl)heterocyclyl, or (C₁ to C₆ alkyl)CN.    -   v. In a further embodiment, R¹ is:

-   -   vi. In yet another embodiment, R¹ is optionally substituted 5-9        membered saturated heterocyclyl.    -   vii. In still a further embodiment, R¹ is of the structure:

-   -    wherein, R³⁴, R³⁵, R³⁶, and R³⁷ are, independently, H, C₁ to C₆        alkyl, or CN; Y is (C(R⁸)₂)_(x), NR⁷(C(R⁸)₂)_(x), O, (S═O), SO₂,        or NR⁷; R⁷ and R⁸ are, independently, H, C₁ to C₆ alkyl, C(O)OH,        (C₁ to C₆ alkyl)CN, (C₁ to C₆ alkyl)C(O)OH, C(O)(C₁ to C₆        alkyl)CN, or CN; and x is 0 to 2.    -   viii. In another embodiment, R¹ is:

-   -   ix. In still a further embodiment, R¹ is of the structure:

-   -    wherein, f, g, h, j, and m are, independently, absent, (CH₂),        CH(R³), Z, or C═O; R³ is H, C(O)OH, or C(O)O(C₁ to C₆ alkyl);        R⁴⁵, R⁴⁶, R⁴⁷, and R⁴⁸ are, independently, H or C₁ to C₆ alkyl;        and Z is O, S, SO, SO₂, or NH.    -   x. In yet another embodiment, R¹ is:

-   -   xi. In a further embodiment, R¹ is a heteroaryl.    -   xii. In yet another embodiment, R¹ is thiophene, benzooxole, or        pyridine.    -   xiii. In still another embodiment, R¹ is a monocyclic C₃ to C₈        cycloalkyl.    -   xiv. In yet a further embodiment, R¹ is cycloheptyl or        cyclohexyl, both optionally substituted with —N(C₁ to C₆        alkyl)(C₁ to C₆ alkyl).    -   xv. In another embodiment, R¹ is piperidine substituted with        C(O)(C₁ to C₆ alkyl)CN.    -   xvi. In still a further embodiment, R¹ is:

-   -   a. In one embodiment, R² is phenyl substituted with C(O)NR⁴R⁵.    -   b. In another embodiment, R² is phenyl substituted with

-   -   c. In a further embodiment, R² is phenyl substituted with NR⁴R⁵.    -   d. In yet another embodiment, R² is phenyl substituted with (C₁        to C₆ alkyl)NR⁴R⁵.    -   e. In another embodiment, R² is phenyl substituted with NR⁴R⁵ or        (C₁ to C₆ alkyl)NR⁴R⁵ and R⁴ and R⁵ are taken together with the        nitrogen atom to which they are attached to form a 6-membered        ring.    -   f. In still a further embodiment, R² is phenyl substituted with        NR⁴R⁵ or (C₁ to C₆ alkyl)NR⁴R⁵ and R⁴ and R⁵ are joined to form        a heterocyclyl of the structure:

-   -    wherein, R¹⁰, R¹, R¹², and R¹³ are, independently, H or C₁ to        C₆ alkyl; R¹⁴ is halogen, OH, C(O)OH, C₁ to C₆ alkoxy, (C₁ to C₆        alkyl)halogen, (C₁ to C₆ alkyl)C(O)OH, C₁ to C₆ hydroxyalkyl, C₃        to C₈ cycloalkyl, (C₁ to C₆ alkyl)C(O)NH₂, (C₁ to C₆        alkyl)C(O)NH(C₁ to C₆ hydroxyalkyl), (C₁ to C₆ alkyl)C(O)N(C₁ to        C₆ hydroxyalkyl)₂, (C₁ to C₆ alkyl)CN, (C₁ to C₆        alkyl)heteroaryl, or heteroaryl; and R¹⁸ is C₁ to C₆        hydroxyalkyl or (C₁ to C₆ alkyl)C(O)OH.    -   g. In yet a further embodiment, R² is phenyl substituted with        NR⁴R⁵ or (C₁ to C₆ alkyl)NR⁴R⁵ and wherein R⁴ and R⁵ are joined        to form an optionally substituted piperidine or diazepane.    -   h. In another embodiment, R² is phenyl substituted with NR⁴R⁵ or        (C₁ to C₆ alkyl)NR⁴R⁵ and R⁴ and R⁵ are joined to form:

-   -   i. In still a further embodiment, R² is phenyl substituted with        NR⁴R⁵ or (C₁ to C₆ alkyl)NR₄R⁵ and R⁴ and R⁵ are joined to form        a heterocyclyl of the structure:

-   -    wherein, a, b, c, d, and e are, independently, absent, (CH₂),        CH(R³), Z, or C═O; R³ is H, C(O)OH, C₁ to C₆ hydroxyalkyl, or        C(O)O(C₁ to C₆ alkyl); R¹⁰, R¹¹, R¹², and R¹³ are,        independently, H or C₁ to C₆ alkyl; and Z is O, S, or NH.    -   j. In yet another embodiment, R² is phenyl substituted with        NR⁴R⁵ or (C₁ to C₆ alkyl)NR⁴R⁵ and R⁴ and R⁵ are joined to form:

-   -   k. In a further embodiment, R² is phenyl substituted with NR⁴R⁵        or (C₁ to C₆ alkyl)NR⁴R⁵ and R⁴ and R⁵ are taken together to        form a heterocyclyl of the structure:

-   -    wherein, R¹⁰, R¹¹, R¹², and R¹³ are, independently, H or C₁ to        C₆ alkyl; Y is O or NR⁹; and R⁹ is H, C₁ to C₆ alkyl, OH,        C(O)OH, C₁ to C₆ hydroxyalkyl, (C₁ to C₆ alkyl)NH₂, (C₁ to C₆        alkyl)N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl), (C₁ to C₆ alkyl)(C₁ to        C₆ alkoxy), C(O)(C₁ to C₆ alkyl)NH₂, (C₁ to C₆ alkyl)C(O)OH,        C(O)(C₁ to C₆ hydroxyalkyl), C(O)(C₁ to C₆ alkyl)CN, (C₁ to C₆        alkyl)CN, (C₁ to C₆ alkyl)halogen, or (C₁ to C₆ alkyl)O(C₁ to C₆        alkyl)C(O)(C₁ to C₆ alkyl)NH₂; wherein 2 hydrogen atoms attached        to the same carbon atom are optionally replaced with ═O.    -   l. In yet another embodiment, R² is phenyl substituted with        NR⁴R⁵ or (C₁ to C₆ alkyl)NR⁴R⁵ and R⁴ and R⁵ are taken together        to form an optionally substituted morpholine or piperazine.    -   m. In still a further embodiment, R² is phenyl substituted with        NR⁴R⁵ or (C₁ to C₆ alkyl)NR⁴R⁵ and R⁴ and R⁵ are taken together        to form:

-   -   n. In another embodiment, R² is phenyl substituted with (C₁ to        C₆ alkyl)NR⁴R⁵.    -   o. In yet a further embodiment, R² is phenyl substituted with        (C₁ to C₆ alkyl)NR⁴R⁵ and R⁴ and R⁵ are (C₁ to C₆ hydroxyalkyl).    -   p. In still another embodiment, R² is phenyl substituted with        (C₁ to C₆ alkyl)NR⁴R⁵ and NR⁴R⁵ is:

-   -   q. In a further embodiment, R² is phenyl substituted with (C₁ to        C₆ alkyl)NR⁴R⁵ and R⁴ and R⁵ are joined to form an optionally        substituted 6-membered ring.    -   r. In yet another embodiment, R² is phenyl substituted with (C₁        to C₆ alkyl)NR⁴R⁵ and NR⁴R⁵ are joined to form the 6-membered        ring:

-   -    wherein, R¹⁴ is H, OH, C(O)OH, C₁ to C₆ alkyl, or (C₁ to C₆        alkyl)CN.    -   s. In another embodiment, R² is phenyl substituted with (C₁ to        C₆ alkyl)NR⁴R⁵ and NR⁴R⁵ are joined to form the 6-membered ring:

-   -    wherein, Y is O or NR⁹; and R⁹ is H, C₁ to C₆ alkyl, OH, C₁ to        C₆ hydroxyalkyl, C(O)(C₁ to C₆ hydroxyalkyl), C(O)(C₁ to C₆        alkyl)CN, (C₁ to C₆ alkyl)CN, (C₁ to C₆ alkyl)NH₂, (C₁ to C₆        alkyl)halogen, C(O)(C₁ to C₆ alkyl)CN or (C₁ to C₆ alkyl)O(C₁ to        C₆ alkyl)C(O)(C₁ to C₆ alkyl)NH₂.    -   t. In still a further embodiment, R² is phenyl substituted with        (C₁ to C₆ alkyl)NR⁴R⁵ and NR⁴R⁵ are joined to form the        6-membered ring

-   -    wherein, a, b, c, d, and e are, independently, absent, (CH₂),        CH(R³), or O; and R³ is H or C(O)OH.    -   u. In yet another embodiment, R² is a heteroaryl substituted        with (C₁ to C₆ alkyl)NR⁴R⁵.    -   v. In still another embodiment, R² is:

-   -   w. In a further embodiment, R² is a heteroaryl substituted with        NR⁴R⁵.    -   x. In still another embodiment, R² is a heteroaryl substituted        with NR⁴R⁵ and the heteroaryl is pyridine.    -   y. In yet a further embodiment, R² is of the structure:

-   -   z. In another embodiment, R² is of the structure:

-   -   _ wherein, R⁸⁰ is OH, —(C₁ to C₆ alkyl)CN, C₁ to C₆        hydroxyalkyl, (C₁ to C₆ alkyl)C(O)NH₂, (C₁ to C₆        alkyl)heterocycle or —(C₁ to C₆ alkyl) C(O)OH.    -   aa. In still a further embodiment, R² is of the structure:

-   -    wherein, p is 1 to 6; and R⁸¹ is H or C(O)OH.    -   bb. In another embodiment, R² is of the structure:

-   -    wherein, R⁹⁰ is H, C₁ to C₆ alkyl, C(O)(C₁ to C₆ alkyl)CN, (C₁        to C₆ alkyl)C(O)OH, or C(O)C₁ to C₆ hydroxyalkyl.    -   cc. In yet another embodiment, wherein R² is phenyl substituted        with one or more C₁ to C₆ alkoxy, (C₁ to C₆ alkyl)halogen, C₁ to        C₆ trifluoroalkoxy, (C₁ to C₆ alkyl)C(O)OH, halogen, optionally        substituted C₃ to C₈ cycloalkyl, optionally substituted        heterocyclyl, optionally substituted heteroaryl, —O—(C₁ to C₆        alkyl)C(O)OH, —O—(C₁ to C₆ alkyl)NR⁴R⁵, —O(optionally        substituted heterocycle), —O(C₁ to C₆ alkyl)N(C₁ to C₆ alkyl)(C₁        to C₆ alkyl), —O(C₁ to C₆ alkyl)NH₂, C₁ to C₆ hydroxyalkyl,        —O(C₁ to C₆ hydroxyalkyl), —O(C₁ to C₆ alkyl)C(O)OH, —C₁ to C₆        alkoxy-C₁ to C₆ alkoxy, —O(heterocycle)(C₁ to C₆ hydroxyalkyl),        —SO₂(C₁ to C₆ alkyl), or —(C₁ to C₆ alkyl)(C₁ to C₆        alkoxy)halogen.    -   dd. In a further embodiment, wherein R² is of the structure:

-   -    wherein, R⁶ is H, (C₁ to C₆ alkyl)C(O)OH, or (C₁ to C₆        alkyl)CN.    -   ee. In still another embodiment, R² is of the structure:

-   -    wherein, z is 1, 2, 3, 4, 5, or 6.    -   ff. In another embodiment, R² is of the structure:

-   -    wherein, R⁶ is H or (C₁ to C₆ alkyl)C(O)OH.    -   gg. In yet a further embodiment, R² is —O(C₁ to C₆ alkyl)NR⁴R⁵.    -   hh. In still another embodiment, R² is of the structure:

-   -    wherein, y is 2 to 6; and R⁵⁰ is H, OH, C₁ to C₆ alkyl, C₁ to        C₆ hydroxyalkyl, or —(C₁ to C₆ alkyl)C(O)OH.    -   ii. In further embodiment, R² is of the structure:

-   -    wherein, m is 2 to 6; y is 0 or 1; Z is O or NR⁶⁰; and R⁶⁰ is        H, C₁ to C₆ alkyl, C₁ to C₆ hydroxyalkyl, —(C₁ to C₆ alkyl)CN,        —(C₁ to C₆ alkyl)C(O)OH, —(C₁ to C₆ alkyl)CONH₂, or —C(O)(C₁ to        C₆ alkyl)OH; wherein 2 hydrogen atoms attached to one carbon        atom of the nitrogen-ring are replaced with an oxo or optionally        substituted 3-8 membered spirocyclic ring.    -   jj. In yet another embodiment, R² is of the structure:

-   -    wherein, r is 2 to 6; and R⁷⁰ is H, C(O)OH or C₁ to C₆        hydroxyalkyl.    -   kk. In still a further embodiment, R² is:

-   -   ll. In another embodiment, R² is aryl substituted with —O—(C₁ to        C₆ alkyl)-heterocycle.        mm. In a further embodiment, R² is:

In one aspect, a compound of Formula (I) is provided, wherein R¹ isNR⁴R⁵, optionally substituted C₁ to C₆ alkoxy, optionally substituted C₆to C₁₄ aryl, optionally substituted heteroaryl, optionally substituted3-10 membered monocyclic or bicyclic cycloalkyl, or optionallysubstituted 3-10 membered monocyclic or bicyclic heterocyclyl. The 3-4membered cycloalkyl and heterocyclyl rings are saturated. Hydrogen atomson the same carbon atom of the cycloalkyl or heterocyclyl are optionallyreplaced with an optionally substituted 3-6 membered cycloalkyl orheterocyclyl to form a spirocycloalkyl or spiroheterocyclyl. In additionor alternatively, hydrogen atoms on the same atom of the cycloalkyl orheterocyclyl are optionally replaced with O to form an oxo substituent.R² is phenyl or 5-6 membered heteroaryl containing at least one N or NHin the backbone, wherein R² is optionally substituted with one or moreR¹⁹ and when R² is 4-pyridyl, the 4-pyridyl lacks a carbonyl substituentat the 2^(nd) position. R¹⁹ is NR⁴R⁵, (C₁ to C₆ alkyl)NR⁴R⁵, C₁ to C₆alkyl, C(O)NR⁴R⁵, C₃ to C₈ cycloalkyl substituted with one or more R²¹,or heterocyclyl substituted with one or more R²¹. R²¹ is (C₁ to C₆alkyl)CN, (C₁ to C₆ alkyl)C(O)OH, (C₁ to C₆ alkyl)C(O)NH₂, (C₁ to C₆alkyl)C(O)NHCH₂CH₂OH, or (C₁ to C₆ alkyl)C(O)N(CH₂CH₂OH)₂. R⁴ and R⁵ areindependently selected from among H, C₁ to C₆ alkyl, C₁ to C₆hydroxyalkyl, and (C₁ to C₆ alkyl)N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl).Alternatively, R⁴ and R⁵ are joined to form an optionally substituted3-8 membered heterocyclyl optionally further containing one or more O,S(O)n, or NR⁹. R⁹ is H, OH, (C₁ to C₆ alkyl)C(O)OH, (C₁ to C₆alkyl)C(O)NH₂, (C₁ to C₆ alkyl)C(O)NHCH₂CH₂OH, (C₁ to C₆alkyl)C(O)N(CH₂CH₂OH)₂, C(O)(C₁ to C₆ alkyl)NH₂, C(O)(C₁ to C₆ alkyl)OH,C₁ to C₆ hydroxyalkyl, or C₁ to C₆ alkyl and n is 0 to 2. In oneembodiment, R⁹ is CH₂CH₂OH. Hydrogen atoms on the same carbon atom ofthe heterocyclyl are optionally replaced with a 3-6 membered cycloalkylor heterocyclyl optionally substituted with one or more R²⁰ to form aspirocycloalkyl or spiroheterocyclyl. R²⁰ is C(O)O(C₁ to C₆ alkyl),C(O)OH, (C₁ to C₆ alkyl)C(O)OH, (C₁ to C₆ alkyl)C(O)NH₂, (C₁ to C₆alkyl)C(O)NHCH₂CH₂OH, or (C₁ to C₆ alkyl)C(O)N(CH₂CH₂OH)₂.Alternatively, or in addition, hydrogen atoms on the same atom of any ofthe heterocyclyls or cycloalkyls of R⁹ are optionally replaced with O toform an oxo substituent; or a pharmaceutically acceptable salt or esterthereof.

In another aspect, a compound of Formula (I) is provided, wherein R¹ isNR⁴R⁵, C₁ to C₆ alkoxy, optionally substituted phenyl, heteroaryl,optionally substituted 3-10 membered cycloalkyl, or optionallysubstituted 3-10 membered monocyclic or bicyclic heterocyclyl. Hydrogenatoms on the same carbon atom of the cycloalkyl or heterocyclyl areoptionally replaced with an optionally substituted 3-6 memberedcycloalkyl or heterocyclyl to form a spirocycloalkyl orspiroheterocyclyl. In addition or alternatively, hydrogen atoms on thesame atom of the cycloalkyl or heterocyclyl are optionally replaced withO to form an oxo substituent. R² is phenyl or pyrazole, wherein R² isoptionally substituted with one or more R¹⁹. R¹⁹ is NR⁴R⁵, (C₁ to C₆alkyl)NR⁴R⁵, C₁ to C₆ alkyl, C(O)NR⁴R⁵, C₃ to C₈ cycloalkyl substitutedwith one or more R²¹, or heterocyclyl substituted with one or more R²¹.R²¹ is (C₁ to C₆ alkyl)CN, (C₁ to C₆ alkyl)C(O)OH, (C₁ to C₆alkyl)C(O)NH₂, (C₁ to C₆ alkyl)C(O)NHCH₂CH₂OH, (C₁ to C₆alkyl)C(O)N(CH₂CH₂OH)₂. R⁴ and R⁵ are (a) independently selected fromamong H, C₁ to C₆ alkyl, C₁ to C₆ hydroxyalkyl, and (C₁ to C₆ alkyl)N(C₁to C₆ alkyl)(C₁ to C₆ alkyl) or (b) joined to form an optionallysubstituted 3-8 membered heterocyclyl optionally further containing oneor more O, S(O)n, or NR⁹. R⁹ is H, OH, C₁ to C₆ hydroxyalkyl, (C₁ to C₆alkyl)C(O)OH, (C₁ to C₆ alkyl)C(O)NH₂, (C₁ to C₆ alkyl)C(O)NHCH₂CH₂OH,(C₁ to C₆ alkyl)C(O)N(CH₂CH₂OH)₂, C(O)(C₁ to C₆ alkyl)NH₂, C(O)(C₁ to C₆alkyl)OH, or C₁ to C₆ alkyl and n is 0 to 2. In one embodiment, R⁹ isCH₂CH₂OH. Hydrogen atoms on the same carbon atom of the heterocyclyl areoptionally replaced with a 3-6 membered cycloalkyl or heterocyclyl toform a spirocycloalkyl or spiroheterocyclyl optionally substituted withone or more R²⁰. R²⁰ is C(O)O(C₁ to C₆ alkyl), C(O)OH, (C₁ to C₆alkyl)C(O)OH, (C₁ to C₆ alkyl)C(O)NH₂, (C₁ to C₆ alkyl)C(O)NHCH₂CH₂OH,or (C₁ to C₆ alkyl)C(O)N(CH₂CH₂OH)₂. Alternatively, or in addition,hydrogen atoms on the same atom of the heterocyclyl (b) or cycloalkylare optionally replaced with O to form an oxo substituent; or apharmaceutically acceptable salt or ester thereof.

In a further aspect, a compound of Formula (I) is provided, wherein R¹is NR⁴R⁵, C₁ to C₆ alkoxy, phenyl optionally substituted with C(O)O(C₁to C₆ alkyl), C(O)OH, O(C₁ to C₃ perfluoroalkyl), C₁ to C₆ alkoxy,halogen, CH₂-heterocyclyl, or CH₂CN, 5-8 membered cycloalkyl,heteroaryl, or 3-10 membered monocyclic or bicyclic heterocyclyloptionally substituted with (C₁ to C₆ alkyl)C(O)OH, C₁ to C₆ alkyl, CN,C(O)OH, or (C₁ to C₆ alkyl)CN. Hydrogen atoms on the same carbon atom ofthe cycloalkyl or heterocyclyl are optionally replaced with anoptionally substituted 3-6 membered cycloalkyl or heterocyclyl to form aspirocycloalkyl or spiroheterocyclyl. In addition or alternatively,hydrogen atoms on the same atom of the cycloalkyl or heterocyclyl areoptionally replaced with O to form an oxo substituent. R² is phenyl orpyrazole, wherein R² is optionally substituted with one R¹⁹. R¹⁹ isNR⁴R⁵, (C₁ to C₆ alkyl)NR⁴R⁵, C₁ to C₆ alkyl, C(O)NR⁴R⁵, C₃ to C₈cycloalkyl substituted with one or more R²¹, or heterocyclyl substitutedwith one or more R²¹. R²¹ is (C₁ to C₆ alkyl)CN, (C₁ to C₆ alkyl)C(O)OH,(C₁ to C₆ alkyl)C(O)NH₂, (C₁ to C₆ alkyl)C(O)NHCH₂CH₂OH, or (C₁ to C₆alkyl)C(O)N(CH₂CH₂OH)₂. R⁴ and R⁵ are (a) independently selected fromamong H, C₁ to C₆ alkyl, C₁ to C₆ hydroxyalkyl, and (C₁ to C₆ alkyl)N(C₁to C₆ alkyl)(C₁ to C₆ alkyl). R⁴ and R⁵ may also be (b) joined to form a5-8 membered heterocyclyl optionally further containing one or two O,S(O)n, or NR⁹. R⁹ is H, OH, C₁ to C₆ hydroxyalkyl (C₁ to C₆alkyl)C(O)OH, C(O)(C₁ to C₆ alkyl)NH₂, C(O)(C₁ to C₆ alkyl)OH, (C₁ to C₆alkyl)C(O)NH₂, (C₁ to C₆ alkyl)C(O)NHCH₂CH₂OH, (C₁ to C₆alkyl)C(O)N(CH₂CH₂OH)₂, or C₁ to C₆ alkyl and n is 0 to 2. In oneembodiment, R⁹ is CH₂CH₂OH. Hydrogen atoms on the same carbon atom ofthe heterocyclyl are optionally replaced with a 3-5 membered cycloalkyloptionally substituted with one or more R²⁰ to form a spirocycloalkyl.R²⁰ is C(O)O(C₁ to C₆ alkyl), C(O)OH, (C₁ to C₆ alkyl)C(O)OH, (C₁ to C₆alkyl)C(O)NH₂, (C₁ to C₆ alkyl)C(O)NHCH₂CH₂OH, or (C₁ to C₆alkyl)C(O)N(CH₂CH₂OH)₂. Alternatively, or in addition, hydrogen atoms onthe same atom of the heterocyclyl (b) or cycloalkyl (b) are optionallyreplaced with O to form an oxo substituent; or a pharmaceuticallyacceptable salt or ester thereof.

Some compounds within the present invention possess one or more chiralcenters, and the present invention includes each separate enantiomer ofsuch compounds as well as mixtures of the enantiomers. Where multiplechiral centers exist in compounds of the present invention, theinvention includes each possible combination of chiral centers within acompound, as well as all possible enantiomeric and diastereomericmixtures thereof. All chiral, diastereomeric, and racemic forms of astructure are intended, unless the specific stereochemistry or isomericform is specifically indicated. It is well known in the art how toprepare optically active forms, such as by resolution of racemic formsor by synthesis from optically active starting materials.

The following definitions are used in connection with the compounds ofthe present invention unless the context indicates otherwise. Ingeneral, the number of carbon atoms present in a given group isdesignated “C_(x)-C_(y)”, where x and y are the lower and upper limits,respectively. For example, a group designated as “C₁-C₆” contains from 1to 6 carbon atoms. The carbon number as used in the definitions hereinrefers to carbon backbone and carbon branching, but does not includecarbon atoms of the substituents, such as alkoxy substitutions and thelike. Unless indicated otherwise, the nomenclature of substituents thatare not explicitly defined herein are arrived at by naming from left toright the terminal portion of the functionality followed by the adjacentfunctionality toward the point of attachment. For example, thesubstituent “arylalkyloxycabonyl” refers to the group (C₆-C₁₄aryl)-(C₁-C₆ alkyl)-O—C(O)—. Terms not defined herein have the meaningcommonly attributed to them by those skilled in the art.

“Alkyl” refers to a hydrocarbon chain that may be a straight chain orbranched chain, containing the indicated number of carbon atoms, forexample, a C₁-C₁₂ alkyl group may have from 1 to 12 (inclusive) carbonatoms in it. Examples of C₁-C₆ alkyl groups include, but are not limitedto, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl,sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. Examples ofC₁-C₈ alkyl groups include, but are not limited to, methyl, propyl,pentyl, hexyl, heptyl, 3-methylhex-1-yl, 2,3-dimethylpent-2-yl,3-ethylpent-1-yl, octyl, 2-methylhept-2-yl, 2,3-dimethylhex-1-yl, and2,3,3-trimethylpent-1-yl. An alkyl group can be unsubstituted orsubstituted with one or more of halogen, NH₂, (alkyl)NH,(alkyl)(alkyl)N—, —N(alkyl)C(O)(alkyl), —NHC(O)(alkyl), —NHC(O)H,—C(O)NH₂, —C(O)NH(alkyl), —C(O)N(alkyl)(alkyl), CN, OH, alkoxy, alkyl,C(O)OH, —C(O)O(alkyl), —C(O)(alkyl), aryl, heteroaryl, heterocyclyl,cycloalkyl, haloalkyl, aminoalkyl-, —OC(O)(alkyl), carboxyamidoalkyl-,and NO₂.

“Alkoxy” refers to the group R—O— where R is an alkyl group, as definedabove. Exemplary C₁-C₆ alkoxy groups include but are not limited tomethoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy. An alkoxygroup can be unsubstituted or substituted with one or more of halogen,OH, alkoxy, NH₂, (alkyl)amino-, di(alkyl)amino-, (alkyl)C(O)N(C₁-C₃alkyl)-, (alkyl)carboxyamido-, HC(O)NH—, H₂NC(O)—, (alkyl)NHC(O)—,di(alkyl)NC(O)—, CN, C(O)OH, (alkoxy)carbonyl-, (alkyl)C(O)—, aryl,heteroaryl, cycloalkyl, haloalkyl, amino(C₁-C₆ alkyl)-,(alkyl)carboxyl-, carboxyamidoalkyl-, or NO₂.

Aryl refers to an aromatic 6 to 14 membered hydrocarbon group. Examplesof a C₆-C₁₄ aryl group include, but are not limited to, phenyl,α-naphthyl, β-naphthyl, biphenyl, anthryl, tetrahydronaphthyl,fluorenyl, indanyl, biphenylenyl, and acenanaphthyl. Examples of aC₆-C₁₀ aryl group include, but are not limited to, phenyl, α-naphthyl,β-naphthyl, biphenyl, and tetrahydronaphthyl. An aryl group can beunsubstituted or substituted with one or more of alkyl, halogen,haloalkyl, alkoxy, haloalkoxy, OH, hydroxyalkyl, —O-(hydroxyalkyl),—O-(alkyl)-C(O)OH, -(alkyl)-(alkoxy)-halogen, NH₂, aminoalkyl-,dialkylamino-, C(O)OH, —C(O)O-(alkyl), —OC(O)(alkyl),—O-(alkyl)-N(alkyl)(alkyl), N-alkylamido-, —C(O)NH₂, (alkyl)amido-, NO₂,(aryl)alkyl, alkoxy, aryloxy, heteroaryloxy, (aryl)amino,(alkoxy)carbonyl-, (alkyl)amido-, (alkyl)amino, aminoalkyl-,alkylcarboxyl-, (alkyl)carboxyamido-, (aryl)alkyl-, (aryl)amino-,cycloalkenyl, di(alkyl)amino-, heteroaryl, (heteroaryl)alkyl-,heterocyclyl, —O-(heterocyclyl), heterocyclyl(alkyl)-,(hydroxyalkyl)NH—, (hydroxyalkyl)₂N, —SO₂(alkyl) or a spiro substituent.

The term “bicycle” or “bicyclic” as used herein refers to a moleculethat features two fused rings, which rings are a cycloalkyl,heterocyclyl, or heteroaryl. In one embodiment, the rings are fusedacross a bond between two atoms. The bicyclic moiety formed therefromshares a bond between the rings. In another embodiment, the bicyclicmoiety is formed by the fusion of two rings across a sequence of atomsof the rings to form a bridgehead. Similarly, a “bridge” is anunbranched chain of one or more atoms connecting two bridgeheads in apolycyclic compound. In another embodiment, the bicyclic molecule is a“spiro” or “spirocyclic” moiety. The spirocyclic group is a carbocyclicor heterocyclic ring which bound through a single carbon atom of thespirocyclic moiety to a single carbon atom of a carbocyclic orheterocyclic moiety. In one embodiment, the spirocyclic group is acycloalkyl and is bound to another cycloalkyl. In another embodiment,the spirocyclic group is a cycloalkyl and is bound to a heterocyclyl. Ina further embodiment, the spirocyclic group is a heterocyclyl and isbound to another heterocyclyl. In still another embodiment, thespirocyclic group is a heterocyclyl and is bound to a cycloalkyl.

“(Aryl)alkyl” refers to an alkyl group, as defined above, wherein one ormore of the alkyl group's hydrogen atoms has been replaced with an arylgroup as defined above. (C₆-C₁₄ aryl)alkyl- moieties include benzyl,benzhydryl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl,2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. An(aryl)alkyl group can be unsubstituted or substituted with one or moreof halogen, CN, NH₂, OH, (alkyl)amino-, di(alkyl)amino-,(alkyl)C(O)N(alkyl)-, (alkyl)carboxyamido-, HC(O)NH—, H₂NC(O)—,(alkyl)NHC(O)—, di(alkyl)NC(O)—, CN, OH, alkoxy, alkyl, C(O)OH,(alkoxy)carbonyl-, (alkyl)C(O)—, aryl, heteroaryl, cycloalkyl,haloalkyl, amino(alkyl)-, (alkyl)carboxyl-, carboxyamidoalkyl-, or NO₂.

“(Alkoxy)carbonyl-” refers to the group alkyl-O—C(O)—. Exemplary (C₁-C₆alkoxy)carbonyl- groups include but are not limited to methoxy, ethoxy,n-propoxy, 1-propoxy, n-butoxy and t-butoxy. An (alkoxy)carbonyl groupcan be unsubstituted or substituted with one or more of halogen, OH,NH₂, (alkyl)amino-, di(alkyl)amino-, (alkyl)C(O)N(alkyl)-,(alkyl)carboxyamido-, HC(O)NH—, H₂NC(O)—, (alkyl)NHC(O)—,di(alkyl)NC(O)—, CN, alkoxy, C(O)OH, (alkoxy)carbonyl-, (alkyl)C(O)—,aryl, heteroaryl, cycloalkyl, haloalkyl, amino(alkyl)-,(alkyl)carboxyl-, carboxyamidoalkyl-, or NO₂.

“(Alkyl)amido-” refers to a —C(O)NH— group in which the nitrogen atom ofsaid group is attached to a C₁-C₆ alkyl group, as defined above.Representative examples of a (C₁-C₆ alkyl)amido- group include, but arenot limited to, —C(O)NHCH₃, —C(O)NHCH₂CH₃, —C(O)NHCH₂CH₂CH₃,—C(O)NHCH₂CH₂CH₂CH₃, —C(O)NHCH₂CH₂CH₂CH₂CH₃, —C(O)NHCH(CH₃)₂,—C(O)NHCH₂CH(CH₃)₂, —C(O)NHCH(CH₃)CH₂CH₃, —C(O)NH—C(CH₃)₃ and—C(O)NHCH₂C(CH₃)₃.

“(Alkyl)amino-” refers to an —NH group, the nitrogen atom of said groupbeing attached to a alkyl group, as defined above. Representativeexamples of an (C₁-C₆ alkyl)amino- group include, but are not limited toCH₃NH—, CH₃CH₂NH—, CH₃CH₂CH₂NH—, CH₃CH₂CH₂CH₂NH—, (CH₃)₂CHNH—,(CH₃)₂CHCH₂NH—, CH₃CH₂CH(CH₃)NH— and (CH₃)₃CNH—. An (alkyl)amino groupcan be unsubstituted or substituted on the alkyl moiety with one or moreof halogen, NH₂, (alkyl)amino-, di(alkyl)amino-, (alkyl)C(O)N(alkyl)-,(alkyl)carboxyamido-, HC(O)NH—, H₂NC(O)—, (alkyl)NHC(O)—,di(alkyl)NC(O)—, CN, OH, alkoxy, alkyl, C(O)OH, (alkoxy)carbonyl-,(alkyl)C(O)—, aryl, heteroaryl, cycloalkyl, haloalkyl, amino(alkyl)-,(alkyl)carboxyl-, carboxyamidoalkyl-, or NO₂.

“Aminoalkyl-” refers to an alkyl group, as defined above, wherein one ormore of the alkyl group's hydrogen atoms has been replaced with —NH₂;one or both H of the NH₂ may be replaced by a substituent.

“Alkylcarboxyl-” refers to an alkyl group, defined above that isattached to the parent structure through the oxygen atom of a carboxyl(C(O)—O—) functionality. Examples of (C₁-C₆ alkyl)carboxyl- includeacetoxy, propionoxy, propylcarboxyl, and isopentylcarboxyl.

“(Alkyl)carboxyamido-” refers to a —NHC(O)— group in which the carbonylcarbon atom of said group is attached to a C₁-C₆ alkyl group, as definedabove. Representative examples of a (C₁-C₆ alkyl)carboxyamido- groupinclude, but are not limited to, —NHC(O)CH₃, —NHC(O)CH₂CH₃,—NHC(O)CH₂CH₂CH₃, —NHC(O)CH₂CH₂CH₂CH₃, —NHC(O)CH₂CH₂CH₂CH₂CH₃,—NHC(O)CH(CH₃)₂, —NHC(O)CH₂CH(CH₃)₂, —NHC(O)CH(CH₃)CH₂CH₃,—NHC(O)—C(CH₃)₃ and —NHC(O)CH₂C(CH₃)₃.

“(Aryl)amino” refers to a radical of formula (aryl)-NH—, wherein aryl isas defined above. “(Aryl)oxy” refers to the group Ar—O— where Ar is anaryl group, as defined above.

“Cycloalkyl” refers to a non-aromatic, saturated, partially saturated,monocyclic, bicyclic or polycyclic hydrocarbon 3 to 12 membered ringsystem. Representative examples of a C₃-C₁₂ cycloalkyl include, but arenot limited to, cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl,decahydronaphthalen-1-yl, octahydro-1H-inden-2-yl,decahydro-1H-benzo[7]annulen-2-yl, and dodecahydros-indacen-4-yl.Representative examples of a C₃-C₁₀ cycloalkyl include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, decahydronaphthalen-1-yl, andoctahydro-1H-inden-2-yl. Representative examples of a C₃-C₈ cycloalkylinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, and octahydropentalen-2-yl. Acycloalkyl can be unsubstituted or substituted with one or more ofhalogen, NH₂, (alkyl)NH, (alkyl)(alkyl)N—, —N(alkyl)C(O)(alkyl),—NHC(O)(alkyl), —NHC(O)H, —C(O)NH₂, —C(O)NH(alkyl),—C(O)N(alkyl)(alkyl), CN, OH, alkoxy, alkyl, C(O)OH, —C(O)O(alkyl),—C(O) alkyl), aryl, heteroaryl, cycloalkyl, haloalkyl, aminoalkyl-,—OC(O)(alkyl), carboxyamidoalkyl-, and NO₂. Additionally, each of anytwo hydrogen atoms on the same carbon atom of the carbocyclic ring canbe replaced by an oxygen atom to form an oxo (═O) substituent.

“Halo” or “halogen” refers to —F, —Cl, —Br and —I.

“C₁-C₆ haloalkyl” refers to a C₁-C₆ alkyl group, as defined above,wherein one or more of the C₁-C₆ alkyl group's hydrogen atoms has beenreplaced with F, Cl, Br, or I. Each substitution can be independentlyselected from F, Cl, Br, or I. Representative examples of an C₁-C₆haloalkyl- group include, but are not limited to, —CH₂F, —CCl₃, —CF₃,CH₂CF₃, —CH₂C₁, —CH₂CH₂Br, —CH₂CH₂I, —CH₂CH₂CH₂F, —CH₂CH₂CH₂C₁,—CH₂CH₂CH₂CH₂Br, —CH₂CH₂CH₂CH₂I, —CH₂CH₂CH₂CH₂CH₂Br, —CH₂CH₂CH₂CH₂CH₂I,—CH₂CH(Br)CH₃, —CH₂CH(C₁)CH₂CH₃, —CH(F)CH₂CH₃ and —C(CH₃)₂(CH₂C₁).

“Heteroaryl” refers to a monocyclic, bicyclic, or polycyclic aromaticring system containing at least one ring atom selected from theheteroatoms oxygen, sulfur and nitrogen. Examples of C₁-C₉ heteroarylgroups include furan, thiophene, indole, azaindole, oxazole, thiazole,isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine,pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole,N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole,1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole,benzothiazole, benzofuran, benzisoxazole, benzimidazole,N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline,quinoline, and isoquinoline. Bicyclic C₁-C₉ hetroaryl groups includethose where a phenyl, pyridine, pyrimidine or pyridazine ring is fusedto a 5 or 6-membered monocyclic heteroaryl ring having one or twonitrogen atoms in the ring, one nitrogen atom together with either oneoxygen or one sulfur atom in the ring, or one O or S ring atom. Examplesof monocyclic C₁-C₄ heteroaryl groups include 2H-tetrazole,3H-1,2,4-triazole, furan, thiophene, oxazole, thiazole, isoxazole,isothiazole, imidazole, and pyrrole. A heteroaryl group can beunsubstituted or substituted with one or more of C₁-C₆ alkyl, halogen,haloalkyl, OH, CN, hydroxyalkyl, NH₂, aminoalkyl-, dialkylamino-,C(O)OH, —C(O)O-(alkyl), —OC(O)(alkyl), N-alkylamido-, —C(O)NH₂,(alkyl)amido-, —NO₂, (aryl)alkyl, alkoxy, aryloxy, heteroaryloxy,(aryl)amino, (alkoxy)carbonyl-, (alkyl)amido-, (alkyl)amino,aminoalkyl-, alkylcarboxyl-, (alkyl)carboxyamido-, (aryl)alkyl-,(aryl)amino-, cycloalkenyl, di(alkyl)amino-, heteroaryl,(heteroaryl)alkyl-, heterocyclyl, hetyerocyclyl(alkyl)-,(hydroxyalkyl)NH—, (hydroxyalkyl)₂N or a spiro substituent.

“Heterocycle” or “heterocyclyl” refers to monocyclic, bicyclic,polycyclic, or bridged head molecules in which at least one ring atom isa heteroatom. A heterocycle may be saturated or partially saturated.Exemplary C₁-C₉ heterocyclyl groups include but are not limited toaziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine,dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene,dithiolane, piperidine, 1,2,3,6-tetrahydropyridine-1-yl,tetrahydropyran, pyran, thiane, thiine, piperazine, azepane, diazepane,oxazine, 5,6-dihydro-4H-1,3-oxazin-2-yl, 2,5-diazabicyclo[2.2.1]heptane,2,5-diazabicyclo[2.2.2]octane, 3,6-diazabicyclo[3.1.1]heptane,3,8-diazabicyclo[3.2.1]octane, 6-oxa-3,8-diazabicyclo[3.2.1]octane,7-oxa-2,5-diazabicyclo[2.2.2]octane,2,7-dioxa-5-azabicyclo[2.2.2]octane,2-oxa-5-azabicyclo[2.2.1]heptane-5-yl, 2-oxa-5-azabicyclo[2.2.2]octane,3,6-dioxa-8-azabicyclo[3.2.1]octane, 3-oxa-6-azabicyclo[3.1.1]heptane,3-oxa-8-azabicyclo[3.2.1]octan-8-yl,5,7-dioxa-2-azabicyclo[2.2.2]octane,6,8-dioxa-3-azabicyclo[3.2.1]octane, 6-oxa-3-azabicyclo[3.1.1]heptane,8-oxa-3-azabicyclo[3.2.1]octan-3-yl,2-methyl-2,5-diazabicyclo[2.2.1]heptane-5-yl,1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl,3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl-,7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl,9-oxa-3-azabicyclo[3.3.1]nonan-3-yl,3-oxa-9-azabicyclo[3.3.1]nonan-9-yl,3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl,4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl, thiazine, dithiane, anddioxane. The contemplated heterocycle rings or ring systems have aminimum of 3 members. Therefore, for example, C₁ heterocyclyl radicalswould include but are not limited to oxaziranyl, diaziridinyl, anddiazirinyl, C₂ heterocyclyl radicals include but are not limited toaziridinyl, oxiranyl, and diazetidinyl, C₉ heterocyclyl radicals includebut are not limited to azecanyl, tetrahydroquinolinyl, andperhydroisoquinolinyl. A heterocyclyl group can be unsubstituted orsubstituted with one or more of alkyl, halogen, alkoxy, haloalkyl, OH,hydroxyalkyl, —C(O)-(hydroxyalkyl), NH₂, aminoalkyl-, dialkylamino-,C(O)OH, —C(O)O-(alkyl), —OC(O)(alkyl), N-alkylamido-, —C(O)NH₂,(alkyl)amido-, —C(O)-(alkyl)-CN, (alkyl)-CN, or NO₂.

“Heterocyclyl(alkyl)-” refers to an alkyl group, as defined above,wherein one or more of the alkyl group's hydrogen atoms has beenreplaced with a heterocycle group as defined above. Heterocyclyl(C₁-C₆alkyl)- moieties include 1-piperazinylethyl, 4-morpholinylpropyl,6-piperazinylhexyl, and the like. A heterocyclyl(alkyl) group can beunsubstituted or substituted with one or more of halogen, NH₂,(alkyl)amino-, di(alkyl)amino-, (alkyl)C(O)N(alkyl)-,(alkyl)carboxyamido-, HC(O)NH—, H₂NC(O)—, (alkyl)NHC(O)—,di(alkyl)NC(O)—, CN, OH, alkoxy, alkyl, C(O)OH, (alkoxy)carbonyl-,(alkyl)C(O)—, 4- to 7-membered monocyclic heterocycle, aryl, heteroaryl,or cycloalkyl.

“Heteroaryl(alkyl)” refers to a heteroaryl which is attached to an alkylgroup and the heteroaryl is defined above.

“Hydroxyalkyl” refers to a alkyl group, as defined above, wherein one ormore of the alkyl group's hydrogen atoms has been replaced with OHgroups. Examples of C₁-C₆ hydroxyalkyl moieties include, for example,—CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH(OH)CH₂OH, —CH₂CH(OH)CH₃,—CH(CH₃)CH₂OH and higher homologs.

“Perfluoroalkyl-” refers to alkyl group, defined above, having two ormore fluorine atoms. Examples of a C₁-C₆perfluoroalkyl- group includeCF₃, CH₂CF₃, CF₂CF₃ and CH(CF₃)₂.

A “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog,cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or gorilla.

With the proviso that when R² is 4-pyridyl, then there cannot be acarbonyl substituent at the 2-position of the 4-pyridyl moiety;

Representative “pharmaceutically acceptable salts” include but are notlimited to, e.g., water-soluble and water-insoluble salts, such as theacetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,bromide, butyrate, calcium, chloride, choline, citrate, edisylate(camphorsulfonate), fumarate, gluconate, glucuronate, glutamate,hydrobromide, hydrochloride, lauryl sulfate, malate, maleate, mandelate,mesylate, palmitate, pantothenate, phosphate, potassium, propionate,p-toluenesulfonate, salicylate, sodium, stearate, succinate, and sulfatesalts.

The following abbreviations are used and have the indicated definitions:ACN is acetonitrile; DMSO is dimethylsulfoxide; DMF isN,N-dimethylformamide; DMF.DMA is dimethylformamide dimethylacetal; TFAis trifluroroacetic acid; mCPBA is meta-chloroperbenzoic acid; RT isroom temperature; THF is tetrahydrofuran; and NMP is N-methylpyrrolidinone.

Methods useful for making the compounds of Formula (I) are set forth inthe Examples below and generalized in Schemes I-III. One of skill in theart will recognize that Schemes 1-III can be adapted to produce thecompounds of Formula (I) and pharmaceutically accepted salts ofcompounds of Formula (I) according to the present invention. In thereactions described, reactive functional groups, such as hydroxy, amino,imino, thio or carboxy groups, where these are desired in the finalproduct, may be protected to avoid unwanted reactions. Conventionalprotecting groups may be used in accordance with standard practice.

Scheme 1 provides the synthesis of compounds of Formula (I). Ethylacetoacetate 1 is converted to the correspondingbis(methylthio)methylene derivative 2 using carbon disulfide, an organicor inorganic base such as K₂CO₃ and a alkylating agent. In oneembodiment, the alkylating agent is an alkyl iodide, alkyl triflate, oralkyl sulfonate. In another embodiment, the alkylating agent is amethylating agent. In a further embodiment, the alkylating agent ismethyl iodide. Reaction of 2 with an R¹-optionally substituted amidinehydrochloride in the presence of a base results in pyrimidine 3. In oneembodiment, the base utilized to form pyrimidine 3 is Et₃N or Hünig'sbase. The alkyl group on the pyrimidine group of compound 3 is thenoxidized using an oxidizing agent. In one embodiment, the oxidation isperformed using SeO₂. The resulting pyrimidine aldehyde 4 is convertedto pyrimido-pyridazinone 5 using hydrazine hydrate or hydrazinehydrochloride. The methyl thio group in compound 5 is oxidized to amethane sulfonyl using meta-chloroperoxybenzoic acid (mCPBA) or hydrogenperoxide/acetic acid. Finally, the methane sulfonyl group of compound 6is replaced with an R²-substituted aniline to provide compound (I). Inone embodiment, the R²-substituted aniline is an aryl or heteroarylsubstituted aniline.

Scheme 2 provides the synthesis of compound IB which are encompassed bythe structure of Formula (I). In this embodiment, ethyl acetoacetate 1is converted to the corresponding bis(methylthio)methylene derivative 2using carbon disulfide, K₂CO₃ and methyl iodide. Reaction of 2 with anR′-substituted benzamidine hydrochloride in the presence of Et₃N resultsin pyrimidine 3a. The methyl group bound to the C-atom of pyrimidine 3ais then oxidized using SeO₂. The resulting pyrimidine aldehyde 4a isconverted to pyrimido-pyridazinone 5a using hydrazine hydrate orhydrazine hydrochloride. The methyl thio group in compound 5a isoxidized to a methane sulfonyl group using mCPBA. Finally, the methanesulfonyl group is replaced with an R″-substituted aniline to givecompound 1B.

Scheme 3 provides the synthesis of compounds IC which are encompassed bythe structure of Formula (I). Treatment of ethyl chloroformate 7 withammonium thiocyanate results in the production of ethyl thiocyanatoformate 8 which upon treatment with ethyl 3-amino crotanoate results incompound 9. Compound 9 is cyclized to compound 10 by treatment with anorganic or inorganic base. In one embodiment the organic or inorganicbase is a strong base. In one embodiment, the strong base is a tertiaryorganic base. In another embodiment, the strong base is aqueous Et₃N.The dichloro pyrimidine 11 is obtained by treating compound 10 with achlorinating agent. In one embodiment, the chlorinating agent is POCl₃.In another embodiment, this transformation can also be carried out byusing other chlorinating agents such as PCl₅, SOCl₂ in the presence ofan organic base such as TEA, tributyl amine, and N,N-dimethylaniline.The 4-position of dichloropyrimidine 11 is then substituted by reactionwith an optionally substituted (R²) aniline to afford compound 12. The2-position of pyrimidine 12 is then R¹-substituted using coupling agentssuch as boronic acids or boronic ester reagents to provide compound 13.The methyl group at position 4 of pyrimidine 13 is then oxidized usingan oxidizing agent such as SeO₂ to provide compound 14. The resultingpyrimidine aldehyde 14 is converted to pyrimido-pyridazinone 1C usinghydrazine hydrate.

Scheme 4 provides the synthesis of compounds ID which are encompassed bythe structure of Formula (I). Treatment of ethyl chloroformate 7 withammonium thiocyanate results in ethyl thiocyanato formate 8 which upontreatment with ethyl 3-amino crotanoate results in compound 9. Compound9 is cyclized to compound 10 as described in Scheme 3, i.e., bytreatment with aqueous Et₃N. The dichloro pyrimidine compound 11 isobtained by treating compound 10 with POCl₃. The 4-position ofdichloropyrimidine 11 is then substituted by reaction with an optionallyR-substituted aniline to afford compound 12a. The 2-position ofpyrimidine compound 12a is then substituted with an R′-substituted arylor heteroaryl group using a boronic acid or an boronic ester reagent toprovide compound 13a. In one embodiment, the boronic acid is(R′-aryl)-B(OH)₂ or (R′-heteroaryl)-B(OH)₂. The methyl at position-4 onpyrimidine 13a is then oxidized using SeO₂. The resulting pyrimidinealdehyde 14a is converted to pyrimido-pyridazinone 1D using hydrazinehydrate.

Scheme 5 provides the synthesis of compound IE which are encompassed bythe structure of Formula (I). Compound 12 is reacted with an optionallysubstituted amine (NHR⁴R⁵) to provide compound 15. The methyl group atthe 4-position of compound 15 is reacted with DMF.DMA to providecompound 16. Compound 17 is obtained by oxidative cleavage of the olefinof compound 16. In one embodiment, oxidative cleavage is performed usingNaIO₄. Finally, pyrimido-pyridazinone IE is obtained by cyclizing thealdehyde 17. In one embodiment, the cyclizaton is performed usinghydrazine, hydrazine hydrate or hydrazine hydrochloride, as describedpreviously.

Scheme 6 provides the synthesis of compounds 1F which are encompassed bythe structure of Formula (I). Compound 12a is reacted with optionallysubstituted amines to result in 15a. The methyl group of 15a is reactedwith DMF.DMA to give compound 16a. The aldehyde 17a is obtained by theoxidative cleavage of the olefin in 16a. In one embodiment, theoxidative cleavage is performed with NaIO₄. Finally, thepyrimido-pyridazinone 1F is obtained by cyclizing aldehyde 17a. In oneembodiment, cyclization is performed using with hydrazine.

Scheme 7 provides the synthesis of compound 1G which are encompassed bythe structure of Formula (I). Compound 10 is reacted with an alkylatingagent to the S-methyl compound 18. In one embodiment, the reacted isperformed under basic conditions. In another embodiment, the alkylatingagent is methyl iodide, ethyl iodide, propyl iodide, dimethylsulfate,among others. Compound 19 is obtained by chlorinating compound 18. Inone embodiment, compound 18 is chlorinated using POCl₃. Compound 19 isthen NR⁴R⁵ substituted with an optionally substituted amine to providecompound 20 [using NHR⁴R⁵?]. The methyl group of compound 20 is reactedwith DMF.DMA to give compound 21. The aldehyde 22 is obtained by theoxidative cleavage of the olefin group in compound 21. In oneembodiment, the oxidative cleavage is performed with NaIO₄.Alternatively, compound 20 may directly converted to the pyrimidinealdehyde 22 by oxidizing the methyl group using SeO₂ or a combination ofCO₂, t-butyl hydroperoxide, and an alcohol such as C₁ to C₆ alkyl)H₂OH.The resulting pyrimidine aldehyde 22 is converted topyrimido-pyridazinone 23 using hydrazine hydrate or hydrazinehydrochloride. The methyl thio group in compound 23 is oxidized to amethane sulfonyl group. In one embodiment compound 23 is reacted withmeta-chloroperoxybenzoic acid (mCPBA) or hydrogen peroxide/acetic acid.Finally, the methane sulfonyl group of compound 24 is replaced withsuitably substituted aniline to provide compound 1G.

Scheme 8 provides the synthesis of compound 1H which is encompassed bythe structure of Formula (I). In this scheme, compound 19 is coupledwith an optionally substituted boronic acid or boronic ester to givecompound 25. In one embodiment, the coupling is performed in thepresence of a coupling agent such as Pd(PPh₃)₄ or PdCl₂(PPh₃)₂. Themethyl group in compound 25 is then oxidized to the correspondingaldehyde. In one embodiment, the oxidation is performed using SeO₂ or acombination of CO₂, t-butyl hydroperoxide, and an alcohol such as C₁ toC₆ alkyl)H₂OH to give compound 26. Compound 26 is converted topyrimido-pyridazinone 27 using hydrazine hydrate or hydrazinehydrochloride. The methyl thio group in compound 27 is then oxidized toa methane sulfonyl group. In one embodiment, the oxidation is performedusing mCPBA or hydrogen peroxide/acetic acid. Finally, the methanesulfonyl group of compound 28 is replaced with suitably substitutedaniline to provide compound 1H.

Pharmaceutical compositions of the invention comprise a compound ofFormula (I) optionally with other pharmaceutically inert or inactiveingredients. In one embodiment, the pharmaceutically inert or inactiveingredient is one or more pharmaceutically acceptable carrier orexcipient. The present invention also contemplates combining thecompound of Formula (I) with one or more therapeutic agents, i.e.,active ingredients, as described below. In a further embodiment, acompound of Formula (I) is combined with one or more inert/inactiveingredients and one or more therapeutic agents.

The pharmaceutical compositions of the invention contain an amount of acompound of Formula (I) that is effective for treating inflammation in asubject. Specifically, the dosage of the compound of Formula (I) toachieve a therapeutic effect will depend on factors such as theformulation, pharmacological potency of the drug, age, weight and sex ofthe patient, condition being treated, severity of the patient'ssymptoms, specific compound of Formula (I), route of delivery, andresponse pattern of the patient. It is also contemplated that thetreatment and dosage of the compound of Formula (I) may be administeredin unit dosage form and that one skilled in the art would adjust theunit dosage form accordingly to reflect the relative level of activity.The decision as to the particular dosage to be employed (and the numberof times to be administered per day) is within the discretion of theordinarily-skilled physician, and may be varied by titration of thedosage to the particular circumstances to produce the desiredtherapeutic effect.

In one embodiment, the therapeutically effective amount is about 0.0001%to about 25% w/w. In another embodiment, the therapeutically effectiveamount is less than about 20% w/w, about 15% w/w, about 10% w/w, about5% w/w, or about 1% w/w. In another embodiment, the therapeuticallyeffective amount is about 0.0001% to about 10% w/w. In a furtherembodiment, the therapeutically effective amount is about 0.005 to about5% w/w. In yet another embodiment, the therapeutically effective amountis about 0.01 to about 5% w/w. In still a further embodiment, thetherapeutically effective amount is about 0.01% w/w, about 0.05% w/w,about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.8%w/w, about 0.9% w/w, about 1% w/w, about 2% w/w, about 3% w/w, about 4%w/w, or about 5% w/w.

The therapeutically effective amounts may be provided on regularschedule, i.e., on a less than daily, weekly, monthly, or yearly basisor on an irregular schedule with varying administration days, weeks,months, etc. Alternatively, the therapeutically effective amount to beadministered may vary. In one embodiment, the therapeutically effectiveamount for the first dose is higher than the therapeutically effectiveamount for one or more of the subsequent doses. In another embodiment,the therapeutically effective amount for the first dose is lower thanthe therapeutically effective amount for one or more of the subsequentdoses. Equivalent dosages may be administered over various time periodsincluding, but not limited to, about every 2 hours, about every 6 hours,about every 8 hours, about every 12 hours, about every 24 hours, aboutevery 36 hours, about every 48 hours, about every 72 hours, about everyweek, about every 2 weeks, about every 3 weeks, about every month, aboutevery 2 months, about every 3 months and about every 6 months. Thenumber and frequency of dosages corresponding to a completed course oftherapy will be determined according to the judgment of a health-carepractitioner. The therapeutically effective amounts described hereinrefer to total amounts administered for a given time period; that is, ifmore than one compound of Formula (I) is administered, thetherapeutically effective amounts correspond to the total amountadministered.

The compound of Formula (I) may be administered by any route, takinginto consideration the specific condition for which it has beenselected. The compounds of Formula (I) may be delivered orally, byinjection (including intravascularly, e.g, intravenously orintra-arterially), inhalation (intranasally and intratracheally),ocularly, transdermally (via simple passive diffusion formulations orvia facilitated delivery using, for example, iontophoresis,microporation with microneedles, radio-frequency ablation or the like),intravascularly, subcutaneously, intramuscularly, sublingually,intracranially, epidurally, rectally, and vaginally, among others.Desirably, the compound of Formula (I) may be administered by injection,transdermally or topically.

In one embodiment, the compound of Formula (I) may be administeredtopically to the eye, e.g., as solutions, suspensions or ointments.Examples of ophthalmically compatible carriers which may be usedinclude, without limitation, an aqueous solution, such as salinesolution, oil solution or ointments containing ophthalmically compatiblepreservatives, surfactants, buffers, and viscosity regulators. Thesecompositions may also contain stabilizing agents, antibacterial agents,and may be manufactured in different dosage units, suitable for ocularadministration. Drug inserts, either soluble or insoluble, may also beused.

In another embodiment, the compound of Formula (I) may be administeredby injection. Solutions for injection or infusion may be prepared asaqueous solutions. Desirably, the compound of Formula (I) is present ina concentration of about 0.001 μg/mL to 1 mg/mL, or this amount may beadjusted higher or lower as needed. These solutions may also containstabilizing agents, antibacterial agents, buffers and may bemanufactured in different dosage unit ampoules or bottles.

In a further embodiment, the compound of Formula (I) may be administeredrectally. Dosage units for rectal administration may be prepared in theform of ointments or suppositories, which contain the compound ofFormula (I) in a mixture with a neutral fat base, or they may beprepared in the form of gelatin-rectal capsules that contain thecompound of Formula (I) in a mixture with, e.g., a vegetable oil orparaffin oil. Ointments, suppositories or creams containing at least onecompound of Formula (I) are useful for the treatment of hemorrhoids.

In yet another embodiment, the compound of Formula (I) may beadministered orally. Dosage units for oral administration include,without limitation, tablets, caplets, capsules, powders, suspensions,microcapsules, dispersible powder, granules, suspensions, syrups,elixirs, and aerosols, which contain the compound of Formula (I)optionally with one or more excipient. In one embodiment, thecompositions are compressed into a tablet or caplet. In anotherembodiment, the tablet or caplet may be administered to the subject. Inanother embodiment, the tablet or caplet may be added to a capsule. In afurther embodiment, the composition containing the compound of Formula(I) is added directly to a capsule. In one embodiment, the capsuleincludes hydroxypropyl methylcellulose, hypromellose capsule, or a hardshell gelatin capsule. In yet another embodiment the tablets or capletsare optionally film-coated using film-coatings known to those of skillin the art. In one embodiment, the film-coating is selected from amongpolymers such as, without limitation, hydroxypropylmethylcellulose,ethyl cellulose, polyvinyl alcohols, and combinations thereof.

Although the compound of Formula (I) may be administered alone, i.e.,neat, it may also be administered in the presence of one or morepharmaceutical carriers that are physiologically compatible. The amountof the pharmaceutical carrier(s) is determined by the solubility andchemical nature of the compound of Formula (I), chosen route ofadministration, and standard pharmacological practice. The carriers maybe in dry (solid) or liquid form and must be pharmaceuticallyacceptable. Liquid pharmaceutical compositions are typically sterilesolutions or suspensions. When liquid carriers are utilized forparenteral administration, they are desirably sterile liquids. Liquidcarriers are typically utilized in preparing solutions, suspensions,emulsions, syrups and elixirs. A variety of suitable liquid carriers isknown and may be readily selected by one of skill in the art. Suchcarriers may include, e.g., dimethylsulfoxide (DMSO), saline, bufferedsaline, cyclodextrin, hydroxypropylcyclodextrin (HPβCD),n-dodecyl-β-D-maltoside (DDM) and mixtures thereof. In one embodiment,the compound of Formula (I) is dissolved a liquid carrier. In anotherembodiment, the compound of Formula (I) is suspended in a liquidcarrier. One of skill in the art of formulations would be able to selecta suitable liquid carrier, depending on the route of administration. Thecompound of Formula (I) may alternatively be formulated in a solidcarrier of which a variety of solid carriers and excipients are known tothose of skill in the art. In one embodiment, the composition may becompacted into a unit dose form, i.e., tablet or caplet. In anotherembodiment, the composition may be added to unit dose form, i.e., acapsule. In a further embodiment, the composition may be formulated foradministration as a powder. The solid carrier may perform a variety offunctions, i.e., may perform the functions of two or more of theexcipients described below. For example, a solid carrier may also act asa flavoring agent, lubricant, solubilizer, suspending agent, filler,glidant, compression aid, binder, disintegrant, or encapsulatingmaterial.

The composition may also be sub-divided to contain appropriatequantities of the compound of Formula (I). For example, the unit dosagecan be packaged compositions, e.g., packeted powders, vials, ampoules,prefilled syringes or sachets containing liquids.

Examples of excipients which may be combined with one or more compoundof Formula (I) include, without limitation, adjuvants, antioxidants,binders, buffers, coatings, coloring agents, compression aids, diluents,disintegrants, emulsifiers (e g., polyoxyethylene fatty acid esters),emollients, encapsulating materials, fillers, flavoring agents,glidants, granulating agents, lubricants, metal chelators,osmo-regulators, pH adjustors (e.g., sodium hydroxide), preservatives,solubilizers, sorbents, stabilizing agents, sweeteners (such assaccharin), surfactants, suspending agents, syrups, thickening agents(e.g., carboxypolymethylene or hydroxypropylmethylcellulose),penetration enhancers (e.g., hydroxypolyethoxydodecane, DMSO, DMAC, DDM,etc) or viscosity regulators (such as polymers to increase viscosity).See, for example, the excipients described in the “Handbook ofPharmaceutical Excipients”, 5^(th) Edition, Eds.: Rowe, Sheskey, andOwen, APhA Publications (Washington, D.C.), Dec. 14, 2005, which isincorporated herein by reference.

In one embodiment, the compositions may be utilized as inhalants. Forthis route of administration, compositions may be prepared as fluid unitdoses using a compound of Formula (I) and a vehicle for delivery by anatomizing spray pump or by dry powder for insufflation.

In another embodiment, the compositions may be utilized as aerosols,i.e., oral or intranasal. For this route of administration, thecompositions are formulated for use in a pressurized aerosol containertogether with a gaseous or liquefied propellant, e.g.,dichlorodifluoromethane, carbon dioxide, nitrogen, propane, and thelike. Also provided is the delivery of a metered dose in one or moreactuations.

In another embodiment, the compositions may be administered by amodified-release delivery device. “Modified-release” as used hereinrefers to delivery of a compound of Formula (I) which is controlled, forexample over a period of at least about 8 hours (e.g., extendeddelivery) to at least about 12 hours (e.g., sustained delivery). Suchdevices may also permit immediate release (e.g., therapeutic levelsachieved in under about 1 hour, or in less than about 2 hours). Those ofskill in the art know suitable modified-release delivery devices. Foruse in such modified-release delivery devices, the compound of Formula(I) is formulated as described herein.

Also contemplated is the administration of the compounds of Formula (I)with other medication(s) or therapeutic agent(s). In one embodiment, thecompounds of Formula (I) are combined with other medications ortherapeutic agents in a single composition. However, the presentinvention is not so limited. In other embodiments, the compounds ofFormula (I) may be administered in one or more separate formulationsfrom other compounds of Formula (I), or other medications or therapeuticagents as described below.

Additionally, one or more agents typically used to treat inflammationmay be used in conjunction with a combination of the invention in themethods, compositions, and kits described herein. Such agents include,but are not limited to, non-steroidal anti-inflammatory drugs.

The compound of Formula (I) may be combined with glucose or dextrosewhen utilized for infusion or as a regional analgesic or anti-pruritic.

Further, the compound of Formula (I) may be combined with thickeningagents to form a jelly, or may also contain penetration enhancers, foruse in topical or dermal applications such as for urogenital topicalprocedures.

Finally, the compound of Formula (I) may be formulated as an ointmentfor administration to accessible mucous membranes.

Also provided herein are kits or packages of pharmaceutical formulationscontaining the compounds of Formula (I) or compositions describedherein. The kits may be organized to indicate a single formulation orcombination of formulations to be taken at each desired time.

Suitably, the kit contains packaging or a container with the compound ofFormula (I) formulated for the desired delivery route. Suitably, the kitcontains instructions on dosing and an insert regarding the compound ofFormula (I).

Optionally, the kit may further contain instructions for monitoringlocal or circulating levels of product and materials for performing suchassays including, e.g., reagents, well plates, containers, markers orlabels, and the like. Such kits are readily packaged in a mannersuitable for treatment of a desired indication. For example, the kit mayalso contain instructions for use of an oral dosage form such as a pill,capsule, patch, spray pump or other delivery device. Other suitablecomponents to include in such kits will be readily apparent to one ofskill in the art, taking into consideration the desired indication andthe delivery route.

The compounds of Formula (I) or compositions described herein can be asingle dose or for continuous or periodic discontinuous administration.For continuous administration, a package or kit can include the compoundof Formula (I) in each dosage unit (e.g., solution, lotion, tablet,pill, drug-eluting patch or other unit described above or utilized indrug delivery), and optionally instructions for administering the dosesless-than-daily, daily, weekly, or monthly, for a predetermined lengthof time or as prescribed. When the compound of Formula (I) is to bedelivered periodically in a discontinuous fashion, a package or kit caninclude placebos during periods when the compound of Formula (I) is notdelivered. When varying concentrations of a composition, of thecomponents of the composition, or the relative ratios of the compoundsof Formula (I) or agents within a composition over time is desired, apackage or kit may contain a sequence of dosage units which provide thedesired variability.

A number of packages or kits are known in the art for dispensingpharmaceutical agents for periodic oral use. In one embodiment, thepackage has indicators for each period.

In another embodiment, the package is a foil or blister package, labeledampoule, vial or bottle.

The packaging means of a kit may itself be geared for administration,such as an inhalant, syringe, pipette, eye dropper, or other suchapparatus, from which the formulation may be applied to an affected areaof the body, such as the lungs, injected into a subject, or even appliedto and mixed with the other components of the kit.

One or more components of these kits also may be provided in dried orlyophilized forms. When reagents or components are provided as a driedform, reconstitution generally is by the addition of a suitable solvent.It is envisioned that the solvent also may be provided in anotherpackage.

The kits of the present invention also will typically include a meansfor containing the vials or other suitable packaging means in closeconfinement for commercial sale such as, e.g., injection or blow-moldedplastic containers into which the desired vials are retained.Irrespective of the number or type of packages and as discussed above,the kits also may include, or be packaged with a separate instrument forassisting with the injection/administration or placement of thecomposition within the body of an animal. Such an instrument may be aninhalant, syringe, pipette, forceps, measuring spoon, eye dropper or anysuch medically approved delivery means.

In one embodiment, a kit is provided and contains a compound of Formula(I). The compound of Formula (I) may be in the presence or absence ofone or more of the carriers or excipients described above. The kit mayoptionally contain instructions for administering the compound ofFormula (I) to a subject having inflammation.

In a further embodiment, a kit is provided and contains a compound ofFormula (I) in a second dosage unit, and one or more of the carriers orexcipients described above in a third dosage unit. The kit mayoptionally contain instructions for administering the compound ofFormula (I) to a subject having inflammation.

As discussed above, the methods, compositions, and kits of the inventioncan be used to treat inflammation resulting from a number of conditions.The term “inflammation” as used herein includes all types ofinflammation. In one embodiment, the inflammation may be acute orchronic. In another embodiment, the inflammation may be nociceptive,dysfunctional, idiopathic, neuropathic, somatic, visceral, and/orprocedural. For example, the inflammation may be from a migraine,gynecological condition, pre-labor or labor, stroke, surgery, neuralgia,sickle cell, interstitial cystitis, urological condition (such asurethritis), dental work/injury, or headache, among other. Inflammationmay also occur in patients with cancer, which may be due to multiplecauses, such as nerve compression and mechanical forces resulting fromtissue distension as a consequence of invasion by a tumor and tumormetastasis into bone or other tissues.

In one embodiment, inflammation results from neuropathy, such aspost-herpetic neuralgia. In still another embodiment, the inflammationresults from a surgery or procedure.

In yet a further embodiment, the inflammation results from an infection,cancer, colitis, cystitis, irritable bowel syndrome, or idiopathicneuropathy.

“Somatic inflammation” includes inflammation in bone, joint, muscle,skin, or connective tissue.

“Central inflammation” includes inflammation arising as a consequence ofbrain trauma, stroke, or spinal cord injury.

“Visceral inflammation” includes inflammation in visceral organs, suchas the respiratory or gastrointestinal tract and pancreas, the urinarytract and reproductive organs. In one embodiment, visceral inflammationresults from tumor involvement of the organ capsule. In anotherembodiment, visceral inflammation from obstruction of hollow viscus.

“Idiopathic inflammation” refers to inflammation which has no underlyingcause or refers to inflammation caused by condition which remainsundiagnosed.

“Dysfunctional inflammation” refers to inflammation which occurs in theabsence of a noxious stimulus, tissue damage or a lesion to the nervoussystem. In one embodiment, dysfunctional inflammation results fromrheumatologic conditions such as arthritis and fibromyalgia, tensiontype headache, irritable bowel disorders and erythermalgia.

“Nociceptive inflammation” includes inflammation caused by noxiousstimuli that threaten to or actually injure body tissues. In oneembodiment, nociceptive inflammation results from a cut, bruise, bonefracture, crush injury, burn, trauma, surgery, labor, sprain, bump,injection, dental procedure, skin biopsy, or obstruction. In anotherembodiment, nociceptive inflammation is located in the skin,musculoskeletal system, or internal organs.

“Neuropathic inflammation” is inflammation due to abnormal processing ofsensory input by the peripheral or central nervous system consequent ona lesion to these systems. In one embodiment, neuropathic inflammationis chronic and non-malignant. In one embodiment, neuropathicinflammation is due to trauma, surgery, herniation of an intervertebraldisk, spinal cord injury, diabetes, infection with herpes zoster(shingles), HIV/AIDS, late-stage cancer, amputation (such asmastectomy), carpal tunnel syndrome, chronic alcohol use, exposure toradiation, and as an unintended side-effect of neurotoxic treatmentagents, such as certain anti-HIV and chemotherapeutic drugs.

“Procedural inflammation” includes refers to inflammation arising from amedical procedure. The medical procedure may include any type ofmedical, dental or surgical procedure. In one embodiment, the proceduralinflammation is postoperative. In another embodiment, the inflammationis associated with an injection, draining an abscess, surgery,dermatological, dental procedure, ophthalmic procedure, arthroscopy anduse of other medical instrumentation, and/or cosmetic surgery.

A “migraine” is a type of headache, typically defined clinically asbeing caused by activation of sensory fibers innervating the meninges ofthe brain.

The term “treat”, “treating”, or any variation thereof is meant toinclude therapy utilized to remedy a health problem or condition in apatient or subject. In one embodiment, the health problem or conditionmay be eliminated permanently or for a short period of time. In afurther embodiment, the health problem or condition may be prevented. Inanother embodiment, the severity of the health problem or condition, orof one or more symptoms characteristic of the health problem orcondition, may be lessened permanently, or for a short period of time.The effectiveness of a treatment of inflammation can be determined usingany standard inflammation index, such as those described herein, or canbe determined based on the patient's subjective inflammation assessment.A patient is considered “treated” if there is a reported reduction ininflammation, or a reduced reaction to stimuli that should causeinflammation.

In one embodiment, the treatment methods described herein includeadministering a compound of Formula (I) to a patient. Additional,optional agents, such as those described above for use in thecombination, may be administered to the patient prior to, concurrentlywith, or subsequent to the compound of Formula (I).

The present invention is further exemplified, but not limited, by thefollowing examples that illustrate the preparation of compounds ofFormula (I) according to the invention

EXAMPLES Example 1:4-(4-morpholinophenylamino)-2-phenylpyrimido[5,4-d]pyridazin-5(6H)-one

a: Ethyl 2-(bis(methylthio)methylene)-3-oxobutanoate

To a solution of ethyl acetoacetate (10 g, 76.9 mmol) in DMF (40 mL) wasadded K₂CO₃ (10.6 g, 76.9 mmol) and the reaction mixture was stirred atRT for 2 hours. Carbon disulfide (8.8 g, 230 mmol) was added, stirringwas continued. After 2 hours, methyl iodide was added and stirring wascontinued for additional 10 hours. The reaction mixture was partitionedbetween ethyl acetate and water, the organic layer washed with water anddried over Na₂SO₄ and the solvent evaporated in vacuum. The crudeproduct was purified by column chromatography over silica gel usingethyl acetate and petroleum ether as eluent to give the desired product(8.8 g). ¹H-NMR 400 Hz (CDCl₃): δ 4.29 (q, J=7.2 Hz, 2H), 2.44 (s, 6H),2.34 (s, 3H), 1.33 (t, J=7.2 Hz, 3H); MS m/z 235 (M+1).

b: Ethyl 4-methyl-6-(methylthio)-2-phenylpyrimidine-5-carboxylate

To a solution of ethyl 2-(bis(methylthio)methylene)-3-oxobutanoate (500mg, 2 mmol) in ethanol was added benzamidine acetate (732 mg, 6 mmol)and triethyl amine (1.41 mL) and the reaction mixture was refluxedovernight. The reaction mixture was concentrated and partitioned betweenethyl acetate and water and the organic layer washed with water anddried over Na₂SO₄ and the solvent evaporated in vacuum. The crudeproduct was purified by column chromatography over silica gel using 1%ethyl acetate in petroleum ether as eluent to give the desired product(350 mg). ¹H-NMR 400 Hz (CDCl₃): δ 8.50 (d, J=7.6 Hz, 2H), 7.50-7.46 (m,3H), 4.45 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 2.65 (s, 3H), 1.44 (t, J=7.2Hz, 3H); MS m/z 288.7 (M+1).

c: Ethyl 4-formyl-6-(methylthio)-2-phenylpyrimidine-5-carboxylate

To a solution of ethyl4-methyl-6-(methylthio)-2-phenylpyrimidine-5-carboxylate (5 g 17.4 mmol)in 1.4-dioxane (50 mL) was added selenium dioxide (9.6 g, 86.5 mmol) andwater (1.5 mL) and the reaction mixture was refluxed for 12 hours.Dioxane was removed in a vacuum and the crude solid suspended in ethylacetate and filtered. The filtrate was concentrated and purified bycolumn chromatography over silica gel using 10% ethyl acetate inpetroleum ether as eluent to give the desired product (3.1 g). ¹H-NMR(400 Hz, CDCl₃): δ 10.10 (s, 1H), 8.54 (d, J=7.2 Hz, 2H), 7.56-7.43 (m,3H), 4.47 (q, J=7.2 Hz, 2H), 2.67 (s, 3H), 2.64 (s, 3H), 1.42 (t, J=7.2Hz, 3H); MS m/z 303.1 (M+1).

d: 4-(methylthio)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one

To a solution of ethyl4-formyl-6-(methylthio)-2-phenylpyrimidine-5-carboxylate (600 mg, 1.98mmol) in ethanol (15 mL) was added hydrazine dihydrochloride (0.2 g,1.98 mmol) and the mixture refluxed for 1 hour. The precipitated solidwas filtered and dried in vacuum. The desired product (520 mg) wasobtained by column chromatography over silica gel usingmethanol/dichloromethane as eluent. ¹H-NMR (400 Hz, DMSO-d₆): δ 13.19(s, 1H), 8.54 (d, J=8.0 Hz, 2H), 8.36 (s, 1H), 7.64-7.58 (m, 3H), 2.67(s, 3H); MS m/z 271.1 (M+1).

e:4-(4-Morpholinophenylamino)-2-phenylpyrimido[5,4-d]pyridazin-5(6H)-one

4-(Methylthio)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one (0.1 g, 0.37mmol) was dissolved in dichloromethane, m-chloro perbenzoic acid (0.19g) was added and the reaction mixture was stirred room temperature for10-12 hours. The solid precipitate was filtered and dried under vacuum.The crude product was dissolved in NMP, 4-(morpholinomethyl)aniline (45mg, 0.25 mmol) was added and the reaction mixture was heated to 60° C.for 30 minutes. The reaction mixture was cooled and ice water was added.The solid precipitate was filtered and dried under vacuum to yield thedesired product (38 mg).

Example 2: Methyl4-(5-oxo-4-(4-(piperazin-1-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)benzoatehydrochloride

a: (Z)-Ethyl 3-amino-2-(ethoxycarbonylcarbamothioyl)but-2-enoate

To a solution of ethyl chloroformate (1 g, 9.2 mmol) in 1,4-dioxanecooled to 0° C. was added ammonium thiocyanate (0.771 g, 10 mmol) andpyridine (0.726 g, 9.2 mmol) and the mixture was stirred at 0° C. for 2hours. The reaction mixture was extracted with diethyl ether, dried overNa₂SO₄ and concentrated in vacuum to give crude ethylisothiocyanatoformate. This crude product was added dropwise over aperiod of 2-3 hours to a solution of ethyl 3-aminocrotanoate (1.19 g,9.2 mmol) in dioxane at 0-10° C. The reaction mixture was quenched withice water and the resulting solid filtered and dried to get the desiredcrude product, which is used without further purification. ¹H NMR (400MHz, CDCl₃): δ 10.52 (s, 1H), 9.51 (s, 1H), 5.25 (s, 1H), 4.21-4.12 (m,4H), 2.26 (s, 3H), 1.29-1.21 (m, 6H); MS m/z 261.1 (M+1).

b: Ethyl 2-hydroxy-4-mercapto-6-methylpyrimidine-5-carboxylate

(Z)-ethyl 3-amino-2-(ethoxycarbonylcarbamothioyl)but-2-enoate wasdissolved in 30% aqueous triethyl amine and the reaction mixture stirredat 70° C. After 2 hours, the reaction mixture was cooled and neutralizedwith glacial acetic acid and the aqueous mixture extracted with EtOAc.The organic layer was washed with water, dried over Na₂SO₄ andconcentrated under vacuum to give the desired product. ¹H NMR (400 MHz,DMSO-d₆): δ 12.54 (s, 1H), 11.85 (s, 1H), 4.21 (q, J=7.6 Hz, 2H), 2.03(s, 3H), 1.24 (t. J=7.6 Hz, 3H); MS m/z 213.1 (M-1).

c: Ethyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate

Ethyl 2-hydroxy-4-mercapto-6-methylpyrimidine-5-carboxylate (1.4 g, 6.54mmol) was taken up in POCl₃ (13.67 mL) at 0° C., tri-n-butylamine wasadded and the mixture heated to 90° C. for 5 hours. The mixture wascooled, poured slowly on to crushed ice and extracted withdichloromethane. The organic layer was washed with water, dried overNa₂SO₄ and concentrated under vacuum. The pure product was obtained bycolumn purification over silica gel using 3% EtOAc/hexane as eluent. ¹HNMR (400 MHz, CDCl₃): δ 4.47 (q, J=6.8 Hz, 2H), 2.57 (s, 3H), 1.42 (t.J=6.8 Hz, 3H); MS m/z 235.1 (M+1).

d: Ethyl4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-chloro-6-methylpyrimidine-5-carboxylate

Ethyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (0.5 g, 2.1 mmol)and tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (0.6 g, 2.06mmol) were dissolved in NMP and stirred at 0° C. for 2 hour. Thereaction mixture was poured onto water and extracted with EtOAc. Theorganic layer was washed with water, dried over Na₂SO₄ and evaporatedunder vacuum to get the desired compound (0.62 g). ¹H NMR (400 MHz,CDCl₃): δ 10.58 (s, 1H), 7.58 (d, J=6.4 Hz, 2H), 7.31 (d, J=6.4 Hz, 2H),4.45 (q, J=6.8 Hz, 2H), 3.56 (s, 2H), 3.41 (m, 4H), 2.69 (s, 3H), 2.47(m, 4H), 1.45 (s, 9H), 1.43 (t, J=6.8 Hz, 3H); MS m/z 490.0 (M+1).

e: Ethyl4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-(4-(methoxycarbonyl)phenyl)-6-methylpyrimidine-5-carboxylate

Ethyl4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-chloro-6-methylpyrimidine-5-carboxylate(0.8 g, 1.63 mmol), K₂CO₃ (0.56 g, 4 mmol), Pd(PPh₃)₄(0.28 g, 0.24 mmol)were dissolved in dioxane/water (20:1), 4-(methoxycarbonyl)phenylboronicacid (0.38 g, 2.1 mmol) was added the mixture was heated to 100° C. for3 hours. The mixture was diluted with water and extracted with EtOAc.The organic layer was concentrated and purified by column chromatographyover silica gel using 30% EtOAc/hexanes as eluent to give the desiredproduct (0.7 g). ¹H NMR (400 MHz, DMSO-d₆): δ 9.88 (s, 1H), 8.43 (d,J=8.0 Hz, 2H), 8.10 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.35 (d,J=8.4 Hz, 2H), 4.39 (q, J=6.8 Hz, 2H), 3.89 (s, 3H), 3.49 (s, 2H), 2.68(m, 4H), 2.50 (s, 3H), 2.33 (m, 4H), 1.91 (t, J=6.8 Hz, 3H), 1.39 (s,9H); MS m/z 590.2 (M+1).

f: Ethyl4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-formyl-2-(4-(methoxycarbonyl)phenyl)pyrimidine-5-carboxylate

Ethyl4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-(4-(methoxycarbonyl)phenyl)-6-methylpyrimidine-5-carboxylate(0.63 g, 1.06 mmol) was dissolved in dioxane (10 mL), SeO₂ (0.6 g, 5.4mmol) and water (0.096 mL) were added and the reaction mixture heated at100° C. for 3.5 hours. The reaction mixture was concentrated in vacuumand the mixture loaded on to a column of silica gel and eluted withMeOH, dichloromethane as eluent, to give the desired compound (0.52 g).¹H NMR (400 MHz, DMSO-d₆): δ 10.18 (s, 1H), 9.53 (s, 1H), 8.56 (d, J=8.4Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4Hz, 2H), 4.39 (q, J=6.8 Hz, 2H), 3.89 (s, 3H), 3.41 (s, 2H), 3.26 (m,4H), 2.35 (m, 4H)), 1.39 (s, 9H), 1.36 (t, J=6.8 Hz, 3H); MS m/z 636.5(M+1).

g: tert-butyl4-(4-(2-(4-(methoxycarbonyl)phenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)benzyl)piperazine-1-carboxylate

Ethyl4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-formyl-2-(4-(methoxycarbonyl)phenyl)pyrimidine-5-carboxylate(0.5 g, 0.82 mmol) was dissolved in ethanol (5 mL), hydrazine hydrate(60 μL, 1.24 mmol) was added and the mixture is refluxed for 2.5 hours.The reaction mixture was cooled to obtain a solid precipitate. Theprecipitate was filtered and the solid dried under vacuum (0.4 g). ¹HNMR (400 MHz, DMSO-d₆): δ 13.41 (s, 1H), 11.52 (s, 1H), 8.52 (d, J=8.4Hz, 2H), 8.34 (s, 1H), 8.13 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.8 Hz, 2H),7.42 (d, J=8.4 Hz, 2H), 3.90 (s, 3H), 3.51 (s, 2H), 3.29 (t, J=4.4 Hz,4H), 2.34 (t, J=4.4 Hz, 4H), 1.39 (s, 9H); MS m/z 572.3 (M+1).

h: Methyl4-(5-oxo-4-(4-(piperazin-1-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)benzoatehydrochloride

Tert-butyl4-(4-(2-(4-(methoxycarbonyl)phenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)benzyl)piperazine-1-carboxylate(0.1 g, 0.175 mmol) was dissolved in dioxane.HCl (5 mL) and stirred atroom temperature for 1.5 hours. The solid obtained was filtered and theresidue washed with EtOAc and dried to give the desired product (40 mg).

Example 3:2-morpholino-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride

a: Ethyl4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-methyl-2-morpholinopyrimidine-5-carboxylate

Ethyl4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-chloro-6-methylpyrimidine-5-carboxylate(0.6 g, 1.23 mmol) was dissolved in NMP (5 mL), morpholine (0.14 mL) wasadded and the mixture was stirred at room temperature for 45 minutes.The reaction mixture was poured into water and extracted with EtOAc. Theorganic layer was washed with water, dried over Na₂SO₄ and evaporated togive the desired product (0.53 g). ¹H NMR (400 MHz, DMSO-d₆): δ 10.48(s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 4.30 (q, J=6.8Hz, 2H), 3.75 (s, 2H), 3.64 (m, 4H), 3.46-3.21 (m, 8H), 2.69 (s, 3H),2.41 (m, 4H), 1.38 (s, 9H), 1.33 (t, J=6.8 Hz, 3H); MS m/z 541.1 (M+1).

b: (E)-ethyl4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-(2-(dimethylamino)vinyl)-2-morpholinopyrimidine-5-carboxylate

Ethyl4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-methyl-2-morpholinopyrimidine-5-carboxylate(350 mg, 0.64 mmol) was dissolved in DMF (5 mL), dimethyl formamidedimethyl acetal (0.26 mL) was added and the mixture was heated to 130°C. for 12 hours. The reaction mixture was poured into water andextracted with EtOAc. The organic layer was washed with water, driedover Na₂SO₄ and evaporated to give the desired product (0.23 g). ¹H NMR(400 MHz, DMSO-d₆): δ 10.44 (s, 1H), 7.94 (d, J=12.2 Hz, 1H), 7.55 (d,J=8.8 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 5.89 (d, J=12.2 Hz, 1H), 4.30 (q,J=6.8 Hz, 2H), 3.80 (s, 2H), 3.75-3.65 (m, 8H), 3.33 (m, 4H), 3.32 (m,6H), 2.41 (m, 4H), 1.38 (s, 9H), 1.32 (t, J=6.8 Hz, 3H); MS m/z 596.4(M+1).

c: Ethyl4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-formyl-2-morpholinopyrimidine-5-carboxylate

(E)-ethyl4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-(2-(dimethylamino)vinyl)-2-morpholinopyrimidine-5-carboxylate(0.2 g, 0.336 mmol) was dissolved in methanol (4 mL) and to this mixtureat room temperature was added a solution of sodium periodate (0.21 g, 1mmol) in methanol (4 mL). The mixture was stirred at room temperaturefor 3 hours and the precipitate filtered. The filtrate was evaporated,diluted with water and extracted with EtOAc. The organic layer was driedover Na₂SO₄ and evaporated in vacuum. The crude product was purified bycolumn chromatography over silica gel using acetone/dichloromethane aseluent. (0.11 g). ¹H NMR (400 MHz, DMSO-d₆): δ 10.07 (s, 1H), 10.02 (s,1H), 7.59 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 4.31 (q, J=6.8 Hz,2H), 3.83 (s, 2H), 3.75-3.65 (m, 8H), 3.33 (m, 4H), 2.32 (m, 4H), 1.38(s, 9H), 1.31 (t, J=6.8 Hz, 3H); MS m/z 555.5 (M+1).

d:2-morpholino-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride

Ethyl4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-formyl-2-morpholinopyrimidine-5-carboxylate(100 mg, 0.18 mmol) was dissolved in ethanol, hydrazine dihydrochloride(28 mg, 26 mmol) was added and the mixture was refluxed for 3 hours. Thesolid precipitated was filtered and dried in vacuum to give the desiredproduct (49 mg).

By repeating the procedures described in the above examples, usingappropriate starting materials, the following compounds of Formula I, asidentified in Table 1, are obtained, together with their spectroscopicdata in Table 2.

TABLE 1 Synthetic Ex Structure IUPAC Name Scheme 1

4-(4-morpholinophenylamino)- 2-phenylpyrimido[4,5-d]-pyridazin-5(6H)-one 1 2

methyl 4-(5-oxo-4-(4-(piperazin- 1-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)benzoate hydrochloride 3 3

2-morpholino-4-(4-(piperazin- 1-ylmethyl)phenylamino)-pyrimido[4,5-d]pyridazin- 5(6H)-one hydrochloride 5 4

4-(4-(morpholinomethyl)- phenylamino)-2-phenyl-pyrimido[4,5-d]pyridazin- 5(6H)-one 1 5

4-(4-(4-ethylpiperazin-1-yl)- phenylamino)-2-phenyl-pyrimido-[4,5-d]pyridazin- 5(6H)-one 1 6

4-(4-((4-ethylpiperazin-1-yl)- methyl)phenylamino)-2-phenyl-pyrimido[4,5-d]pyridazin- 5(6H)-one 1 7

2-phenyl-4-(4-(piperazin-1-yl- methyl)phenylamino)pyrimido-[4,5-d]pyridazin-5(6H)-one hydrochloride 1 8

2-phenyl-4-(4-(piperazin-1-yl)- phenylamino)pyrimido[4,5-d]-pyridazin-5(6H)-one 1 9

4-(4-(morpholine-4-carbonyl)- phenylamino)-2-phenyl-pyrimido-[4,5-d]pyridazin- 5(6H)-one 1 10

4-(4-(bis(2-hydroxyethyl)- amino)phenylamino)-2-phenyl-pyrimido[4,5-d]pyridazin- 5(6H)-one 1 11

4-(4-(4-(2-aminoacetyl)- piperazin-1-yl)phenylamino)-2-phenylpyrimido[4,5-d]- pyridazin-5(6H)-one hydrochloride 1 12

2-(4-(4-(5-oxo-2-phenyl-5,6- dihydropyrimido[4,5-d]-pyridazin-4-ylamino)phenyl)- piperazin-1-yl)acetic acid 1 13

1-(4-(5-oxo-2-phenyl-5,6- dihydropyrimido[4,5-d]-pyridazin-4-ylamino)phenyl)- piperidine-4-carboxylic acid 1 14

4-(4-(4-(2-aminoacetyl)- piperazin-1-yl)phenylamino)-2-phenylpyrimido[4,5-d]- pyridazin-5(6H)-one 1 15

N-(2-(dimethylamino)ethyl)- N-methyl-4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]- pyridazin-4-ylamino)benzamide 1 16

4-(4-(2-oxo-1,7-diazaspiro- [3.5]nonan-7-yl)phenylamino)-2-phenylpyrimido[4,5-d]- pyridazin-5(6H)-one 1 17

4-(4-(2-oxa-7-azaspiro[3.5]- nonan-7-yl)phenylamino)-2-phenylpyrimido[4,5-d]- pyridazin-5(6H)-one 1 18

4-(4-morpholinophenylamino)- 2-(6-azaspiro[2.5]octan-6-yl)-pyrimido[4,5-d]pyridazin- 5(6H)-one 5 19

6-(4-(5-oxo-2-phenyl-5,6- dihydropyrimido[4,5-d]-pyridazin-4-ylamino)phenyl)- 6-azaspiro[2.5]octane-1- carboxylic acid 120

ethyl 6-(4-(5-oxo-2-phenyl- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-ylamino)phenyl)- 6-azaspiro[2.5]octane-1- carboxylate 1 21

6-(4-(5-oxo-2-phenyl-5,6- dihydropyrimido[4,5-d]-pyridazin-4-ylamino)benzyl)- 6-azaspiro[2.5]octane-1- carboxylic acid 122

sodium 6-(4-(5-oxo-2-phenyl- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-ylamino)phenyl)- 6-azaspiro[2.5]octane-1- carboxylate 1 23

4-(4-(2-oxa-7-azaspiro[3.5]- nonan-7-ylmethyl)phenyl-amino)-2-phenylpyrimido[4,5- d]pyridazin-5(6H)-one 1 24

4-(4-(piperazin-1-ylmethyl)- phenylamino)-2-(thiophen-3-yl)pyrimido[4,5-d]pyridazin- 5(6H)-one hydrochloride 3 25

6-(5-oxo-4-(4-(piperazin-1- ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)-6-azaspiro-[2.5]octane-1-carboxylic acid hydrochloride 5 26

4-(4-(4-ethylpiperazin-1-yl)- phenylamino)-2-morpholino-pyrimido[4,5-d]pyridazin- 5(6H)-one 5 27

4-(5-oxo-4-(4-(piperazin-1- ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)benzoic acid hydrochloride 3 28

4-(4-(4-ethylpiperazin-1-yl)- phenylamino)-2-(4-(trifluoro-methoxy)phenyl)pyrimido- [4,5-d]pyridazin-5(6H)-one 3 29

methyl 4-(4-(4-morpholino- phenylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)benzoate 3 30

4-(4-(piperazin-1-ylmethyl)- phenylamino)-2-(piperidin-1-yl)pyrimido[4,5-d]pyridazin- 5(6H)-one hydrochloride 5 31

2-(3-methoxyphenyl)-4-(4- (piperazin-1-ylmethyl)phenyl-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one hydrochloride 3 32

2-(piperazin-1-yl)-4-(4- (piperazin-1-ylmethyl)phenyl-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one dihydrochloride 5 33

2-(benzo[d][1,3]dioxol-5-yl)- 4-(4-(piperazin-1-ylmethyl)-phenylamino)pyrimido[4,5-d]- pyridazin-5(6H)-one hydrochloride 3 34

2-(1-(4-(5-oxo-2-phenyl-5,6- dihydropyrimido[4,5-d]-pyridazin-4-ylamino)phenyl)- piperidin-4-yl)acetic acid 1 35

1-(4-(5-oxo-2-phenyl-5,6- dihydropyrimido[4,5-d]-pyridazin-4-ylamino)benzyl)- piperidine-4-carboxylic acid 1 36

2-(2-methoxyphenyl)-4-(4- (piperazin-1-ylmethyl)phenyl-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one hydrochloride 3 37

4-(4-(4-ethylpiperazin-1-yl)- phenylamino)-2-(thiophen-3-yl)pyrimido[4,5-d]pyridazin- 5(6H)-one hydrochloride 3 38

9-(5-oxo-4-(4-(piperazin-1- ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)-3,9-diazaspiro-[5.5]undecane-2,4-dione hydrochloride 5 39

6-(4-(5-oxo-2-(thiophen-3-yl)- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-ylamino)phenyl)- 6-azaspiro[2.5]octane-1- carboxylic acid 340

2-(4-chlorophenyl)-4-(4- (piperazin-1-ylmethyl)phenyl-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one hydrochloride 3 41

2-(4-methoxyphenyl)-4-(4- (piperazin-1-ylmethyl)-phenylamino)pyrimido[4,5-d]- pyridazin-5(6H)-one hydrochloride 3 42

6-(4-((2-morpholino-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- 6-azaspiro[2.5]octane-1- carboxylic acid 543

2-(1-(5-oxo-4-((4-(piperazin- 1-ylmethyl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetic acidhydrochloride 5 44

2-(1-oxidothiomorpholino)- 4-((4-(piperazin-1-ylmethyl)-phenyl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one hydrochloride 5 45

2-(4-methylpiperazin-1-yl)-4- ((4-(piperazin-1-ylmethyl)-phenyl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one hydrochloride 5 46

6-(4-((2-(4-methoxyphenyl)- 5-oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid 3 47

6-(4-((2-(3-methoxyphenyl)- 5-oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid 3 48

4-((4-(piperazin-1-ylmethyl)- phenyl)amino)-2-(pyrrolidin-1-yl)pyrimido[4,5-d]pyridazin- 5(6H)-one hydrochloride 5 49

2-(dimethylamino)-4-((4- (piperazin-1-ylmethyl)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one hydrochloride 5 50

2-ethoxy-4-((4-(piperazin-1- ylmethyl)phenyl)amino)-pyrimido[4,5-d]pyridazin- 5(6H)-one hydrochloride 5 51

1-(5-oxo-4-((4-(piperazin-1- ylmethyl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidine-4- carboxylic acidhydrochloride 5 52

2-(azepan-1-yl)-4-((4-(piperazin- 1-ylmethyl)phenyl)amino)-pyrimido[4,5-d]pyridazin- 5(6H)-one hydrochloride 5 53

6-(4-((2-(2-methoxyphenyl)- 5-oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid 3 54

2-(diisopropylamino)-4-((4- (piperazin-1-ylmethyl)phenyl)-amino)pyrimido[4,5-d]pyridazin- 5(6H)-one hydrochloride 5 55

2-(4-(morpholinomethyl)- phenyl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)- pyrimido[4,5-d]pyridazin- 5(6H)-onehydrochloride 3 56

1-(5-oxo-4-((4-(piperazin-1- ylmethyl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidine-4- carbonitrilehydrochloride 5 57

2-(4-ethylpiperazin-1-yl)-4- ((4-(piperazin-1-ylmethyl)-phenyl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one hydrochloride 5 58

4-((1-(2-morpholinoethyl)- 1H-pyrazol-4-yl)amino)-2-phenylpyrimido[4,5-d]- pyridazin-5(6H)-one 1 59

2-(1,4-diazepan-1-yl)-4-((4- (piperazin-1-ylmethyl)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one dihydrochloride 5 60

2-(azepan-1-yl)-4-((4- morpholinophenyl)amino)-pyrimido[4,5-d]pyridazin- 5(6H)-one 5 61

2-methoxy-4-((4-(piperazin-1- ylmethyl)phenyl)amino)-pyrimido[4,5-d]pyridazin- 5(6H)-one hydrochloride 5 62

6-(4-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- 6-azaspiro[2.5]octane-1- carboxylic acid 563

2-phenyl-4-((1-(2-(piperazin- 1-yl)ethyl)-1H-pyrazol-4-yl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one hydrochloride 1 64

4-((1-(2-(4-methylpiperazin- 1-yl)ethyl)-1H-pyrazol-4-yl)amino)-2-phenylpyrimido- [4,5-d]pyridazin-5(6H)-one 1 65

4-((1-(2-(4-ethylpiperazin-1- yl)ethyl)-1H-pyrazol-4-yl)-amino)-2-phenylpyrimido- [4,5-d]pyridazin-5(6H)-one 1 66

6-(4-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 5 67

2-(azepan-1-yl)-4-((3,4,5- trimethoxyphenyl)amino)-pyrimido[4,5-d]pyridazin- 5(6H)-one 5 68

2-(azepan-1-yl)-4-((4- (morpholine-4-carbonyl)- phenyl)amino)pyrimido-[4,5-d]pyridazin-5(6H)-one 5 69

2-(1-(4-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- piperidin-4-yl)acetic acid 5 70

2-(1-(4-((2-(4-(cyanomethyl)- piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenyl)-piperidin-4-yl)acetic acid 5 71

2-(1-((4-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenyl)-piperidin-4-yl)acetic acid 5 72

6-(4-((2-(1,4-diazepan-1-yl)- 5-oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid hydrochloride 5 73

6-(4-((2-(4-(cyanomethyl)- piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 5 74

6-(4-((2-(4-cyanopiperidin-1- yl)-5-oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid 5 75

2-(1-(4-((2-(4-cyanopiperidin- 1-yl)-5-oxo-5,6-dihydro-pyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4- yl)acetic acid5 76

1-(4-((2-(4-cyanopiperidin-1- yl)-5-oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- benzyl)piperidine-4-carboxylic acid 5 77

2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)- piperidin-4-yl)acetic acid 5 78

1-(4-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)benzyl)-piperidine-4-carboxylic acid 5 79

6-(4-((2-cyclohexyl-5-oxo-5,6- dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- 6-azaspiro[2.5]octane-1- carboxylic acid 380

2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- piperidin-4-yl)acetonitrile 5 81

6-(4-((2-cycloheptyl-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- 6-azaspiro[2.5]octane-1- carboxylic acid 382

2-(1-(4-((5-oxo-2-phenyl-5,6- dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- piperidin-4-yl)acetonitrile 1 83

4-((4-((4-(2-hydroxy-2- methylpropanoyl)piperazin-1-yl)methyl)phenyl)amino)-2- phenylpyrimido[4,5-d]- pyridazin-5(6H)-one 184

2-(azepan-1-yl)-4-((4-((4-(2- hydroxy-2-methylpropanoyl)-piperazin-1-yl)methyl)phenyl)- amino)pyrimido[4,5-d]-pyridazin-5(6H)-one 3 85

2-(azepan-1-yl)-4-((4-((4- methylpiperazin-1-yl)methyl)-phenyl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 3 86

2-(4-(4-((5-oxo-2-phenyl-5,6- dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- piperidin-1-yl)acetic acid 1 87

2-(4-(4-((5-oxo-2-phenyl-5,6- dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- cyclohexyl)acetic acid 3 88

2-(1-(4-((2-(azocan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- piperidin-4-yl)acetic acid 5 89

2-(azepan-1-yl)-4-((4-(2- (piperazin-1-yl)ethoxy)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one hydrochloride 5 90

2-(1-(4-((2-cycloheptyl-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- piperidin-4-yl)acetic acid 3 91

2-(4-(4-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- cyclohexyl)acetic acid 5 92

4-(4-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenoxy)- butanoic acid 5 93

2-(azepan-1-yl)-4-((4-(2- morpholinoethoxy)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 5 94

4-((4-(2-morpholinoethoxy)- phenyl)amino)-2-phenyl-pyrimido[4,5-d]pyridazin- 5(6H)-one 3 95

2-(azepan-1-yl)-4-((4-(2-(4- methylpiperazin-1-yl)ethoxy)-phenyl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 5 96

2-(1-(2-(4-((2-(azepan-1-yl)- 5-oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- phenoxy)ethyl)piperidin-4- yl)acetic acid5 97

2-(1-(5-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)pyridin- 2-yl)piperidin-4-yl)acetonitrile 5 98

1-(2-(4-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenoxy)- ethyl)piperidine-4-carboxylic acid 5 99

2-(1-(5-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)pyridin- 2-yl)piperidin-4-yl)acetamide 5 100

2-(1-(4-((2-(4-(2-cyanopropan- 2-yl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenyl)-piperidin-4-yl)acetic acid 5 101

2-(1-(5-((5-oxo-2-phenyl-5,6- dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)pyridin- 2-yl)piperidin-4-yl)acetonitrile 3 102

2-(1-(5-((5-oxo-2-phenyl-5,6- dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)pyridin- 2-yl)piperidin-4-yl)acetamide 3 103

2-(1-(5-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetonitrile 5 104

2-(azepan-1-yl)-4-((4- (piperazine-1-carbonyl)- phenyl)amino)pyrimido-[4,5-d]pyridazin-5(6H)-one hydrochloride 5 105

2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)- phenyl)piperidin-4-yl)- acetamide 5 106

2-(4-(2-(4-((2-(azepan-1-yl)- 5-oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- phenoxy)ethyl)piperazin-1- yl)acetic acid3 107

2-(azepan-1-yl)-4-((4-(2- (piperazin-1-yl)ethoxy)-phenyl)amino)pyrimido- [4,5-d]pyridazin-5(6H)-one 5 108

2-(1-(5-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)pyridin-2- yl)piperidin-4-yl)acetic acid 5 109

2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)- phenyl)piperidin-4-yl)-N-(2-hydroxyethyl)acetamide 5 110

2-(azepan-1-yl)-4-((4-(((2S,5S)- 5-(hydroxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)amino)- pyrimido[4,5-d]pyridazin- 5(6H)-one 5 111

2-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)- phenyl)piperazin-1-yl)-2- methylpropanenitrile5 112

2-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- piperazin-1-yl)-2-methyl- propanamide 5113

2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- piperidin-4-yl)acetonitrile 5 114

2-(1-(5-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetonitrile 5 115

2-(azepan-1-yl)-4-((4-(2-(4- (2-hydroxy-2-methylpropanoyl)-piperazin-1-yl)ethoxy)phenyl)- amino)pyrimido[4,5-d]-pyridazin-5(6H)-one 5 116

2-(1-(5-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid 5 117

2-(1-(4-((2-(3,5-dimethyl- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenyl)-piperidin-4-yl)acetic acid 5 118

2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)- phenyl)piperidin-4-yl)-N,N-bis(2-hydroxyethyl)acetamide 5 119

2-methyl-2-(1-(4-((5-oxo-2- phenyl-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- phenyl)piperidin-4-yl)- propanenitrile 3120

2-(4-(2-(4-((2-(azepan-1-yl)- 5-oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- phenoxy)ethyl)piperazin-1-yl)-2-methylpropanenitrile 5 121

2-(1-(4-((2-(2,6-dimethyl- morpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenyl)-piperidin-4-yl)acetic acid 3 122

4-((4-(((2S,5S)-5-(hydroxy- methyl)-1,4-dioxan-2-yl)-methoxy)phenyl)amino)- 2-phenylpyrimido[4,5-d]- pyridazin-5(6H)-one 3123

2-((1S,4S)-4-(4-((2-(azepan-1- yl)-5-oxo-5,6-dihydro-pyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)cyclohexyl)- acetic acid 5124

(2R,5S)-5-((4-((2-(azepan-1- yl)-5-oxo-5,6-dihydro-pyrimido[4,5-d]pyridazin-4- yl)amino)phenoxy)methyl)-1,4-dioxane-2-carboxylic acid 5 125

2-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)- phenyl)piperazin-1-yl)acetic acid 5 126

2-(1-(3-(4-((2-(azepan-1-yl)- 5-oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- phenoxy)propyl)piperidin-4- yl)acetic acid5 127

6-(4-((2-(cyclohexylamino)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)- phenyl)spiro[2.5]octane-1- carboxylic acid 5128

6-(4-((5-oxo-2-(piperidin-1- yl)-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)- phenyl)spiro[2.5]octane-1- carboxylic acid 5129

2-((1R,4R)-4-(4-((2-(azepan- 1-yl)-5-oxo-5,6-dihydro-pyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)cyclohexyl)- acetic acid 5130

3-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)- phenyl)piperidin-4-yl)- propanoic acid 5 131

2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)- phenyl)piperidin-4-yl)- cyclopropanecarboxylicacid 5 132

3-(1-(4-((5-oxo-2-phenyl-5,6- dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- piperidin-4-yl)propanoic acid 3 133

6-(4-((2-(4-fluorophenyl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)- 6-azaspiro[2.5]octane-1- carboxylic acid3 134

6-(5-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)pyridin- 2-yl)-6-azaspiro[2.5]octane-1- carboxylicacid 5 135

6-(4-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)-2- fluorophenyl)-6-azaspiro-[2.5]octane-1-carboxylic acid 5 136

2-(azepan-1-yl)-4-((4-(3- (piperazin-1-yl)propoxy)-phenyl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 5 137

6-(5-((5-oxo-2-phenyl-5,6- dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)pyridin- 2-yl)-6-azaspiro[2.5]octane-1- carboxylicacid 3 138

6-(4-((5-oxo-2-(pyridin-4-yl)- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- 6-azaspiro[2.5]octane-1- carboxylic acid 3139

2-(azepan-1-yl)-4-((4-(4-(2- hydroxypropan-2-yl)piperidin-1-yl)phenyl)amino)pyrimido- [4,5-d]pyridazin-5(6H)-one 5 140

2-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)- phenyl)piperazin-1-yl)-2- methylpropanoic acid5 141

6-(4-((2-(azocan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- 6-azaspiro[2.5]octane-1- carboxylic acid 5142

2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)- phenyl)piperidin-4-yl)-2- methylpropanoic acid5 143

2-methyl-2-(1-(4-((5-oxo-2- phenyl-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- phenyl)piperidin-4-yl)- propanoic acid 2144

2-(4-(5-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)- pyridin-2-yl)piperazin-1-yl)- acetic acid 7 145

2-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)- phenyl)1,4-diazepan-1-yl)- acetic acid 7 146

2-(1-(4-((4-(4-(2-hydroxy- propan-2-yl)piperidin-1-yl)-phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]-pyridazin-2-yl)piperidin-4- yl)acetonitrile 7 147

3-(1-(4-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenyl)-piperidin-4-yl)propanoic acid 7 148

6-(5-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)pyridin-2-yl)-6-azaspiro[2.5]octane-1- carboxylic acid 7 149

1-(5-oxo-4-((4-(2-(piperazin- 1-yl)ethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidine-4- carbonitrile 7150

2-(1-(5-oxo-4-((4-(2-(piperazin- 1-yl)ethoxy)phenyl)amino)-5,6-dihydropyrimido-[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile7 151

2-(azepan-1-yl)-4-((4-(2-(4- ethylpiperazin-1-yl)ethoxy)-phenyl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 152

2-phenyl-4-((4-(2-(piperazin- 1-yl)ethoxy)phenyl)amino)-pyrimido[4,5-d]pyridazin- 5(6H)-one 8 153

4-((4-(2-(piperazin-1-yl)- ethoxy)phenyl)amino)-2-(piperidin-1-yl)pyrimido- [4,5-d]pyridazin-5(6H)-one 7 154

2-(4-(4-((5-oxo-2-(piperidin- 1-yl)-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)- amino)phenyl)-1,4-diazepan- 1-yl)acetic acid 7155

6-(4-((2-(4-methylpiperidin- 1-yl)-5-oxo-5,6-dihydro-pyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro-[2.5]octane-1-carboxylic acid 7 156

2-(4-methylpiperidin-1-yl)-4- ((4-(2-(piperazin-1-yl)ethoxy)-phenyl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one hydrochloride 7 157

2-(azepan-1-yl)-4-((4-(2-(3- oxopiperazin-1-yl)ethoxy)-phenyl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 158

6-(2-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)- phenoxy)ethyl)-6-azaspiro-[2.5]octane-1-carboxylic acid 7 159

2-(azepan-1-yl)-4-((4-(2- (diethylamino)ethoxy)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 160

2-(cyclohexyl(methyl)amino)- 4-((4-(2-(piperazin-1-yl)-ethoxy)phenyl)amino)pyrimido- [4,5-d]pyridazin-5(6H)-one 7 161

2-(1-(4-((2-(cyclohexyl- (methyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)-phenyl)piperidin-4-yl)acetic acid 7 162

2-(4-(4-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenyl)-piperazin-1-yl)acetic acid 7 163

2-(1-(4-((2-(3-methoxyphenyl)- 5-oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- phenyl)piperidin-4-yl)- acetonitrile 8 164

4-((4-(2-(1,4-diazepan-1-yl)- ethoxy)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 165

2-(azepan-1-yl)-4-((4-(3- oxopiperazin-1-yl)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 166

2-(3-methoxyphenyl)-4-((4- (2-(piperazin-1-yl)ethoxy)-phenyl)amino)pyrimido- [4,5-d]pyridazin-5(6H)-one 8 167

2-(azepan-1-yl)-4-((4-(2- (dimethylamino)ethoxy)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 168

2-(azepan-1-yl)4-((4-(2- (piperidin-4-yl)ethoxy)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 169

2-(1-(5-oxo-4-((4-(2-(piperidin- 4-yl)ethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile7 170

6-(4-((2-(cyclohexyl(methyl)- amino)-5-oxo-5,6-dihydro-pyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro-[2.5]octane-1-carboxylic acid 7 171

4-((4-(2-(1,4-diazepan-1-yl)- ethoxy)phenyl)amino)-2-(piperidin-1-yl)pyrimido- [4,5-d]pyridazin-5(6H)-one 7 172

2-(azepan-1-yl)-4-((4-(2-(4- hydroxypiperidin-1-yl)ethoxy)-phenyl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 173

2-(azepan-1-yl)-4-((4-(3- (piperazin-1-yl)propyl)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 174

2-(1-(5-oxo-4-((4-(3-(piperazin- 1-yl)propyl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7175

2-(azepan-1-yl)-4-((4-(4-ethyl- 3-oxopiperazin-1-yl)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 176

2-morpholino-4-((4-(2- (piperazin-1-yl)ethoxy)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 5 177

2-(2,6-dimethylmorpholino)- 4-((4-(2-(piperazin-1-yl)-ethoxy)phenyl)amino)pyrimido- [4,5-d]pyridazin-5(6H)-one 5 178

2-(1-(4-((4-(4-ethyl-3-oxo- piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido- [4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 179

2-(azepan-1-yl)-4-((4-(3-(4- hydroxypiperidin-1-yl)propyl)-phenyl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 180

2-(azepan-1-yl)-4-((4-(4- ethylpiperazin-1-yl)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 181

4-((6-(2-(piperazin-1-yl)- ethoxy)pyridin-3-yl)amino)-2-(piperidin-1-yl)pyrimido- [4,5-d]pyridazin-5(6H)-one 7 182

2-(azepan-1-yl)-4-((6-(2- (piperazin-1-yl)ethoxy)pyridin-3-yl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 183

4-((4-(2-(4-hydroxypiperidin- 1-yl)ethoxy)phenyl)amino)-2-(piperidin-1-yl)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 184

2-(azepan-1-yl)-4-((4-(2-(4- hydroxy-4-methylpiperidin-1-yl)ethoxy)phenyl)amino)- pyrimido[4,5-d]pyridazin- 5(6H)-one 7 185

2-(1-(4-((4-(2-(4-hydroxy-4- methylpiperidin-1-yl)ethoxy)-phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]-pyridazin-2-yl)piperidin-4- yl)acetonitrile 7 186

2-(azepan-1-yl)-4-((4-(4- hydroxypiperidin-1-yl)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 187

2-(1-(4-((4-(4-ethylpiperazin- 1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile7 188

2-(azepan-1-yl)-4-((4-(2- (diisopropylamino)ethoxy)-phenyl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 189

2-(1-(4-((4-(4-hydroxypiperidin- 1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7190

2-(azepan-1-yl)-4-((4-(4-(2- hydroxyethyl)piperazin-1-yl)-phenyl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 191

2-(1-(4-((4-(4-(2-hydroxy- ethyl)piperazin-1-yl)phenyl)-amino)-5-oxo-5,6-dihydro- pyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 192

2-(azepan-1-yl)-4-((4-(piperazin- 1-yl)phenyl)amino)pyrimido-[4,5-d]pyridazin-5(6H)-one 7 193

2-(1-(5-oxo-4-((4-(piperazin- 1-yl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7194

2-(azepan-1-yl)-4-((4-(4-(3- hydroxypropyl)piperidin-1-yl)phenyl)amino)pyrimido[4, 5-d]pyridazin-5(6H)-one 7 195

2-(azepan-1-yl)-4-((4-(4-(2- hydroxyethyl)piperidin-1-yl)phenyl)amino)pyrimido[4, 5-d]pyridazin-5(6H)-one 7 196

2-(1-(4-((4-(4-(2-hydroxy- ethyl)piperidin-1-yl)phenyl)-amino)-5-oxo-5,6-dihydro- pyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 197

2-(1-(4-((4-(2-(4-ethylpiperazin- 1-yl)ethyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 198

2-(azepan-1-yl)-4-((4-(2- (piperazin-1-yl)ethyl)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 199

4-((4-(2-aminoethoxy)phenyl)- amino)-2-(azepan-1-yl)pyrimido-[4,5-d]pyridazin-5(6H)-one 7 200

2-(1-(4-((4-(2-aminoethoxy)- phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7201

2-(azepan-1-yl)-4-((4-(2-(4- hydroxypiperidin-1-yl)ethyl)-phenyl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 202

2-(azepan-1-yl)-4-((4-(4- (hydroxymethyl)piperidin-1-yl)phenyl)amino)pyrimido[4, 5-d]pyridazin-5(6H)-one 7 203

2-(azepan-1-yl)-4-((4-(2-(4- (hydroxymethyl)piperidin-1-yl)ethoxy)phenyl)amino)- pyrimido[4,5-d]pyridazin- 5(6H)-one 7 204

2-(1-(2-(4-((2-(azepan-1-yl)- 5-oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- piperidin-1-yl)ethyl)piperidin-4-yl)acetonitrile 7 205

2-(1-(4-((4-(4-(3-hydroxy- propyl)piperidin-1-yl)phenyl)-amino)-5-oxo-5,6-dihydro- pyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 206

2-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- piperazin-1-yl)acetonitrile 7 207

2-(1-(4-((4-(4-(cyanomethyl)- piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido- [4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 208

3-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- phenyl)piperazin-1-yl)- propanoic acid 7209

2-(azepan-1-yl)-4-((4-(2-(4- ethylpiperazin-1-yl)ethyl)-phenyl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 210

2-(azepan-1-yl)-4-((4-(2-(4- hydroxy-4-methylpiperidin-1-yl)ethyl)phenyl)amino)- pyrimido[4,5-d]pyridazin- 5(6H)-one 7 211

2-(azepan-1-yl)-4-((4-(2-(4- (2-hydroxyethyl)piperazin-1-yl)ethyl)phenyl)amino)- pyrimido[4,5-d]pyridazin- 5(6H)-one 7 212

2-(1-(4-((4-(2-(4-(2- hydroxyethyl)piperazin-1-yl)ethyl)phenyl)amino)-5- oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-2-yl)- piperidin-4-yl)acetonitrile 7 213

2-(4-(4-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenyl)-piperazin-1-yl)-2-methyl- propanoic acid 7 214

2-(azepan-1-yl)-4-((4-(4-(2- hydroxy-2-methylpropanoyl)-piperazin-1-yl)phenyl)amino)- pyrimido[4,5-d]pyridazin- 5(6H)-one 7 215

3-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)- phenyl)piperazin-1-yl)-3- oxopropanenitrile 7216

2-(1-(4-((4-(4-(hydroxymethyl)- piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido- [4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 217

2-(azepan-1-yl)-4-((6-(4- hydroxypiperidin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 218

2-(1-(4-((4-(2-(4-(hydroxy- methyl)piperidin-1-yl)ethoxy)-phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]-pyridazin-2-yl)piperidin-4- yl)acetonitrile 7 219

(phosphonooxy)methyl 6-(4- ((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylate 7 220

3-(4-(4-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenyl)-piperazin-1-yl)propanoic acid 7 221

2-(azepan-1-yl)-4-((6-(piperazin- 1-yl)pyridin-3-yl)amino)-pyrimido[4,5-d]pyridazin- 5(6H)-one 7 222

2-(azepan-1-yl)-4-((4-(2-(2- hydroxyethyl)-2H-tetrazol-5-yl)phenyl)amino)pyrimido[4, 5-d]pyridazin-5(6H)-one 7 223

2-(1-(4-((4-(4-(2-hydroxy-2- methylpropanoyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]-pyridazin-2-yl)piperidin-4- yl)acetonitrile 7 224

2-(1-(4-((4-(2-(diethylamino)- ethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile7 225

2-(azepan-1-yl)-4-((4-(2-ethyl- 2H-tetrazol-5-yl)phenyl)amino)-pyrimido[4,5-d]pyridazin- 5(6H)-one 7 226

2-(1-(4-((4-(2-ethyl-2H- tetrazol-5-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido- [4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 227

4-((4-(2H-tetrazol-5-yl)phenyl)- amino)-2-(azepan-1-yl)-pyrimido[4,5-d]pyridazin- 5(6H)-one 7 228

2-(1-(4-((6-(4-ethylpiperazin- 1-yl)pyridin-3-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 229

2-(azepan-1-yl)-4-((6-(4- ethylpiperazin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 230

2-(4-(5-oxo-4-((4-(2- (piperazin-1-yl)ethoxy)- phenyl)amino)-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperazin-1- yl)acetonitrile 7231

2-(1-(5-oxo-4-((6-(piperazin- 1-yl)pyridin-3-yl)amino)-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7232

2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- piperidin-3-yl)acetic acid 7 233

2-(1-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- piperidin-3-yl)acetic acid 7 234

3-(4-(5-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- pyridin-2-yl)piperazin-1-yl)-3-oxopropanenitrile 7 235

2-(5-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- phenyl)-2H-tetrazol-2-yl)acetic acid 7 236

2-(azepan-1-yl)-4-((6-(4-(2- hydroxyethyl)piperidin-1-yl)pyridin-3-yl)amino)- pyrimido[4,5-d]pyridazin- 5(6H)-one 7 237

3-(4-(5-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)pyridin-2-yl)piperazin-1-yl)-3-oxo- propanenitrile 7 238

2-(azepan-1-yl)-4-((6-(4-(2- hydroxy-2-methylpropanoyl)-piperazin-1-yl)pyridin-3-yl)- amino)pyrimido[4,5-d]- pyridazin-5(6H)-one7 239

2-(azepan-1-yl)-4-((4-(2-(4- (2-hydroxyethyl)piperazin-1-yl)ethoxy)phenyl)amino)- pyrimido[4,5-d]pyridazin- 5(6H)-one 7 240

3-(4-(4-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenyl)-piperazin-1-yl)-3-oxopropane- nitrile 7 241

2-(5-(4-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenyl)-2H-tetrazol-2-yl)acetic acid 7 242

2-(azepan-1-yl)-4-((6-(4- methylpiperazin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 243

2-(1-(4-((6-(4-methylpiperazin- 1-yl)pyridin-3-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile7 244

4-((4-(4-((2H-tetrazol-5-yl)- methyl)piperidin-1-yl)phenyl)-amino)-2-(azepan-1-yl)- pyrimido-[4,5-d]pyridazin- 5(6H)-one 7 245

2-(1-(4-((4-(2H-tetrazol-5- yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7246

2-(1-(4-((4-(4-((2H-tetrazol-5- yl)methyl)piperidin-1-yl)-phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]-pyridazin-2-yl)piperidin-4- yl)acetonitrile 7 247

2-(azepan-1-yl)-4-((4-(4- methylpiperazin-1-yl)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 248

2-(1-(4-((4-(4-methylpiperazin- 1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7249

2-(1-(5-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)acetic acid 7 250

2-(1-(4-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl))amino)phenyl)-piperidin-3-yl)acetic acid 7 251

2-(1-(4-((6-(4-(2-hydroxy-2- methylpropanoyl)piperazin-1-yl)pyridin-3-yl)amino)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-2-yl)piperidin-4- yl)acetonitrile 7 252

4-((6-(4-((2H-tetrazol-5-yl)- methyl)piperidin-1-yl)pyridin-3-yl)amino)-2-(azepan-1-yl)- pyrimido[4,5-d]pyridazin- 5(6H)-one 7 253

2-(1-(4-((6-(4-((2H-tetrazol-5- yl)methyl)piperidin-1-yl)-pyridin-3-yl)amino)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-2-yl)piperidin-4- yl)acetonitrile 7 254

2-(4-(4-((2-(azepan-1-yl)-5- oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-4-yl)amino)- phenoxy)piperidin-1-yl)acetic acid 7 255

2-(azepan-1-yl)-4-((4-(4-(2- methoxyethyl)piperazin-1-yl)phenyl)amino)pyrimido- [4,5-d]pyridazin-5(6H)-one 7 256

2-(1-(4-((4-(4-(2-methoxyethyl)- piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido- [4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 257

2-(1-(4-((4-(4-(2-aminoethyl)- piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido- [4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 258

2-(azepan-1-yl)-4-((4-(1- (hydroxymethyl)-6-azaspiro-[2.5]octan-6-yl)phenyl)amino)- pyrimido[4,5-d]pyridazin- 5(6H)-one 7 259

2-(1-(4-((4-(1-(hydroxymethyl)- 6-azaspiro[2.5]octan-6-yl)-phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]-pyridazin-2-yl)piperidin-4- yl)acetonitrile 7 260

2-(azepan-1-yl)-4-((4-(4-(3- hydroxypropyl)piperazin-1-yl)phenyl)amino)pyrimido- [4,5-d]pyridazin-5(6H)-one 7 261

2-(1-(4-((4-(4-(3-hydroxy- propyl)piperazin-1-yl)phenyl)-amino)-5-oxo-5,6-dihydro- pyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 262

2-(4-(4-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenoxy)-piperidin-1-yl)acetic acid 7 263

2-(azepan-1-yl)-4-((4-(4-(2- hydroxyethyl)-1,4-diazepan-1-yl)phenyl)amino)pyrimido- [4,5-d]pyridazin-5(6H)-one 7 264

2-(1-(4-((4-(4-(2-hydroxyethyl)- 1,4-diazepan-1-yl)phenyl)-amino)-5-oxo-5,6-dihydro- pyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 265

2-(azepan-1-yl)-4-((4-(4-(1- hydroxy-2-methylpropan-2-yl)piperazin-1-yl)phenyl)- amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7266

2-(1-(4-((4-(4-(1-hydroxy-2- methylpropan-2-yl)piperazin-1-yl)phenyl)amino)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-2-yl)piperidin-4- yl)acetonitrile 7 267

2-(azepan-1-yl)-4-((4-(4-(2- (dimethylamino)ethyl)piperazin-1-yl)phenyl)amino)pyrimido- [4,5-d]pyridazin-5(6H)-one 7 268

2-(1-(4-((4-(4-(2-(dimethyl- amino)ethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]-pyridazin-2-yl)piperidin-4- yl)acetonitrile 7 269

2-(azepan-1-yl)-4-((4-(2-(4- ethylpiperazin-1-yl)-2-oxoethoxy)phenyl)amino)- pyrimido[4,5-d]pyridazin- 5(6H)-one 7 270

2-(1-(4-((4-(2-(4-ethylpiperazin- 1-yl)-2-oxoethoxy)phenyl)-amino)-5-oxo-5,6-dihydro- pyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 271

2-(1-(4-((4-(2-(4-methyl- piperazin-1-yl)-2-oxoethoxy)-phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]-pyridazin-2-yl)piperidin-4- yl)acetonitrile 7 272

2-(azepan-1-yl)-4-((4-(3-(2- hydroxyethyl)piperidin-1-yl)phenyl)amino)pyrimido- [4,5-d]pyridazin-5(6H)-one 7 273

2-(azepan-1-yl)-4-((4-(4-(2,3- dihydroxypropyl)piperazin-1-yl)phenyl)amino)pyrimido- [4,5-d]pyridazin-5(6H)-one 7 274

2-(1-(4-((4-(4-(2,3-dihydroxy- propyl)piperazin-1-yl)phenyl)-amino)-5-oxo-5,6-dihydro- pyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 275

2-(azepan-1-yl)-4-((4-(4-(2- fluoroethyl)piperazin-1-yl)phenyl)amino)pyrimido- [4,5-d]pyridazin-5(6H)-one 7 276

2-(1-(4-((4-(4-(2-fluoroethyl)- piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido- [4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 277

2-(azepan-1-yl)-4-((6-(3-hydro- piperidin-1-yl)pyridin-3-yl)-amino)pyrimido[4,5-d]-pyridazin-5(6H)-one 7 278

2-(1-(4-((6-(3-hydroxypiperidin- 1-yl)pyridin-3-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile7 279

2-(azepan-1-yl)-4-((4-(4,4- difluoropiperidin-1-yl)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 280

2-(1-(4-((4-(4,4-difluoro- piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido- [4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 281

2-(azepan-1-yl)-4-((4-(3- hydroxypiperidin-1-yl)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 282

2-(1-(4-((4-(3-hydroxypiperidin- 1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7283

2-(azepan-1-yl)-4-((4-(2-(4- methylpiperazin-1-yl)-2-oxoethoxy)phenyl)amino)- pyrimido[4,5-d]pyridazin- 5(6H)-one 7 284

2-(1-(4-((4-(3-(hydroxymethyl)- piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido- [4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 285

2-(azepan-1-yl)-4-((4-(3- (hydroxymethyl)piperidin-1-yl)phenyl)amino)pyrimido- [4,5-d]pyridazin-5(6H)-one 7 286

2-(1-(4-((4-(3-(2-hydroxyethyl)- piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido- [4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 287

2-(1-(4-((4-(4-methoxypiperidin- 1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7288

2-(azepan-1-yl)-4-((4-(4- methoxypiperidin-1-yl)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 289

2-(azepan-1-yl)-4-((4-(4- fluoropiperidin-1-yl)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 290

2-(1-(4-((4-(4-fluoropiperidin- 1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile7 291

2-(1-(4-((4-((1-(2-hydroxy- ethyl)piperidin-4-yl)oxy)-phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]-pyridazin-2-yl)piperidin-4- yl)acetonitrile 7 292

2-(azepan-1-yl)-4-((4-(piperidin- 4-yloxy)phenyl)amino)pyrimido-[4,5-d]pyridazin-5(6H)-one hydrochloride 7 293

2-(1-(4-((4-(2-hydroxyethoxy)- phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7294

2-(azepan-1-yl)-4-((4-(2- hydroxyethoxy)phenyl)amino)-pyrimido[4,5-d]pyridazin- 5(6H)-one 7 295

2-(1-(4-((4-(3-hydroxypropoxy)- phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7296

2-(azepan-1-yl)-4-((4-(3- hydroxypropoxy)phenyl)-amino)pyrimido[4,5-d]-pyridazin-5(6H)-one 7 297

2-(1-(4-((4-(4-(1-hydroxy-2- methylpropan-2-yl)-1,4-diazepan-1-yl)phenyl)amino)- 5-oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-2-yl)piperidin- 4-yl)acetonitrile 7 298

2-(azepan-1-yl)-4-((4-(4-(2- fluoroethyl)piperidin-1-yl)phenyl)amino)pyrimido- [4,5-d]pyridazin-5(6H)-one 7 299

2-(1-(4-((4-(4-(2-fluoroethyl)- piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido- [4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonilrile 7 300

2-(1-(4-((3,5-dimethoxyphenyl)- amino)-5-oxo-5,6-dihydro-pyrimido[4,5-d]pyridazin-2- yl)piperidin-4-yl)acetonitrile 7 301

2-(1-(5-oxo-4-((4-(trifluoro- methoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7302

2-(azepan-1-yl)-4-((3,5- dimethoxyphenyl)amino)-pyrimido[4,5-d]pyridazin- 5(6H)-one 7 303

2-(azepan-1-yl)-4-((4-(trifluoro- methoxy)phenyl)amino)-pyrimido[4,5-d]pyridazin- 5(6H)-one 7 304

3-(4-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenyl)- propanoic acid 7 305

3-(4-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenyl)- propanoic acid 7306

2-(azepan-1-yl)-4-((4-(bis(2- hydroxyethyl)amino)phenyl)-amino)pyrimido[4,5-d]- pyridazin-5(6H)-one 7 307

2-(1-(4-((4-(bis(2-hydroxyethyl)- amino)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile7 308

2-(azepan-1-yl)-4-((4-(3- hydroxypropyl)phenyl)amino)-pyrimido[4,5-d]pyridazin- 5(6H)-one 7 309

2-(1-(4-((4-(3-hydroxypropyl)- phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7310

2-(azepan-1-yl)-4-((3-(hydroxy- methyl)phenyl)amino)pyrimido-[4,5-d]pyridazin-5(6H)-one 7 311

2-(1-(4-((3-(hydroxymethyl)- phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7312

2-(1-(4-((4-fluorophenyl)amino)- 5-oxo-5,6-dihydropyrimido-[4,5-d]pyridazin-2-yl)piperidin- 4-yl)acetonitrile 7 313

2-(azepan-1-yl)-4-((4-fluoro- phenyl)amino)pyrimido-[4,5-d]pyridazin-5(6H)-one 7 314

2-(azepan-1-yl)-4-((4-((1- hydroxy-2-methylpropan-2-yl)oxy)phenyl)amino)pyrimido- [4,5-d]pyridazin-5(6H)-one 7 315

2-(1-(4-((4-((1-hydroxy-2- methylpropan-2-yl)oxy)-phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]-pyridazin-2-yl)piperidin-4- yl)acetonitrile 7 316

2-(4-((2-(azepan-1-yl)-5-oxo- 5,6-dihydropyrimido[4,5-d]-pyridazin-4-yl)amino)phenoxy)- 2-methylpropanoic acid 7 317

2-(4-((2-(4-(cyanomethyl)- piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-4-yl)amino)phenoxy)- 2-methylpropanoicacid 7 318

2-(azepan-1-yl)-4-((3,4- dimethoxyphenyl)amino)-pyrimido[4,5-d]pyridazin- 5(6H)-one 7 319

2-(1-(4-((3,4-dimethoxyphenyl)- amino)-5-oxo-5,6-dihydro-pyrimido[4,5-d]pyridazin-2- yl)piperidin-4-yl)acetonitrile 7 320

2-(azepan-1-yl)-4-((3-methoxy- phenyl)amino)pyrimido[4,5-d]-pyridazin-5(6H)-one 7 321

2-(1-(4-((3-methoxyphenyl)- amino)-5-oxo-5,6-dihydro-pyrimido[4,5-d]pyridazin-2- yl)piperidin-4-yl)acetonitrile 7 322

2-(azepan-1-yl)-4-((4-(2- hydroxyethyl)phenyl)amino)-pyrimido[4,5-d]pyridazin- 5(6H)-one 7 323

2-(1-(4-((4-(2-hydroxyethyl)- phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7324

2-(azepan-1-yl)-4-((4-(2- methoxyethoxy)phenyl)amino)-pyrimido[4,5-d]pyridazin- 5(6H)-one 7 325

2-(1-(4-((4-(2-methoxyethoxy)- phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7326

2-(1-(5-oxo-4-((3,4,5- trimethoxyphenyl)amino)-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonilrile7 327

2-(azepan-1-yl)-4-(benzo[d]- [1,3]dioxol-5-ylamino)pyrimido-[4,5-d]pyridazin-5(6H)-one 7 328

2-(1(4-(benzo[d][1,3]dioxol- 5-ylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7329

2-(azepan-1-yl)-4-((4-((1-(2- hydroxyethyl)piperidin-4-yl)oxy)phenyl)amino)pyrimido- [4,5-d]pyridazin-5(6H)-one 7 330

sodium (2-(4-(cyanomethyl)- piperidin-1-yl)-4-((4-(4-hydroxypiperidin-1-yl)phenyl)- amino)-5-oxopyrimido[4,5-d]-pyridazin-6(5H)-yl)methyl phosphate 7 331

2-(azepan-1-yl)-4-((4-(hydroxy- methyl)phenyl)amino)pyrimido-[4,5-d]pyridazin-5(6H)-one 7 332

2-(1-(4-((4-(hydroxymethyl)- phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7333

2-(1-(4-((4-(methylsulfonyl)- phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7334

2-(azepan-1-yl)-4-((4-(methyl- sulfonyl)phenyl)amino)pyrimido-[4,5-d]pyridazin-5(6H)-one 7 335

2-(1-(4-((1H-benzo[d][1,2,3]- triazol-5-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7336

2-(1-(5-oxo-4-((2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)amino)-5,6-dihydro- pyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 7 337

2-(1-(4-((4-(3-fluoropropyl)- phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7338

2-(1-(4-((4-(difluoromethoxy)- phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]- pyridazin-2-yl)piperidin-4- yl)acetonitrile 7339

4-((1H-benzo[d][1,2,3]triazol- 5-yl)amino)-2-(azepan-1-yl)-pyrimido[4,5-d]pyridazin- 5(6H)-one 7

The following compounds in Table A are prepared by one of skill in theart using the above-noted Schemes, descriptions, and Examples 1-339.

TABLE A Structure IUPAC Name

2-(2,6-dimethylpiperidin-1-yl)-4-((4- (piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one

2-(1-(4-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid

6-(4-((2-(2,6-dimethylpiperidin-1-yl)-5- oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)- 6-azaspiro[2.5]octane-1-carboxylicacid

2-(1-(4-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)phenyl)piperidin-4-yl)acetonitrile

2-(2,6-dimethylpiperidin-1-yl)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-one

2-(1-(5-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4- yl)acetic acid

2-(3,5-dimethylpiperidin-1-yl)-4-((4- (piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one

2-(1-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid

6-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane- 1-carboxylic acid

2-(1-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)phenyl)piperidin-4-yl)acetonitrile

2-(3,5-dimethylpiperidin-1-yl)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-one

2-(1-(5-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4- yl)acetic acid

2-(2,6-dimethylmorpholino)-4-((4- (piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one

2-(1-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid

6-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid

2-(1-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)phenyl)piperidin-4-yl)acetonitrile

2-(2,6-dimethylmorpholino)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-one

2-(1-(5-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4- yl)acetic acid

2-(diisopropylamino)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one

2-(1-(4-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)aceticacid

6-(4-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid

2-(1-(4-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile

2-(diisopropylamino)-4-((4-(4-(2-hydroxy- 2-methylpropanoyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-one

2-(1-(5-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid

2-(2-methylpiperidin-1-yl)-4-((4- (piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one

2-(1-(4-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid

6-(4-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid

2-(1-(4-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile

4-((4-(4-(2-hydroxy-2- methylpropanoyl)piperidin-1-yl)phenyl)amino)-2-(2-methylpiperidin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one

2-(1-(5-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid

1-(4-((2-(azepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid

1-(4-((2-(azepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid

4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one

4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one

2-(1-(4-((2-cycloheptyl-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid

1-(4-((2-cycloheptyl-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid

6-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid

2-(1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid

1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid

1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid

1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-3-carbonitrile

2-(1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)acetic acid

1-(4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-3-carbonitrile

1-(4-((2-cycloheptyl-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid

4-((4-((4-(2H-tetrazol-5-yl)piperidin-1- yl)methyl)phenyl)amino)-2-cycloheptylpyrimido[4,5-d]pyridazin- 5(6H)-one

2-(1-(4-((2-cycloheptyl-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)acetic acid

4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-2- cycloheptylpyrimido[4,5-d]pyridazin-5(6H)-one

1-(4-((2-(4-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid

1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-carbonitrile

1-(4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-carbonitrile

1-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid

2-(1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile

2-(1-(4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile

1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid

1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid

2-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-1-yl)acetonitrile

2-(1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4- yl)acetic acid

2-(4-(4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-1-yl)acetonitrile

6-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid

2-(1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)aceticacid

1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid

1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid

6-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid

2-(1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4- yl)acetic acid

1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid

1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid

3-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-1-yl)-3-oxopropanenitrile

2-(1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4- yl)acetic acid

4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-2-(4-(2- isocyanoacetyl)piperazin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one

6-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylic acid

2-(1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4- yl)acetic acid

1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid

1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid

3-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-1-yl)-3-oxopropanenitrile

2-(1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4- yl)acetic acid

4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-2-(1-(2- isocyanoacetyl)piperidin-4-yl)pyrimido[4,5-d]pyridazin-5(6H)-one

TABLE 2 Physical Data Ex # Structure ¹H-NMR in DMSO-d₆ at 400 Hz (δ) MSm/z 1

13.32 (s, 1H), 11.32 (s, 1H), 8.42 (d, J = 6.7 Hz, 2H), 8.29 (s, 1H),7.76 (d, J = 8.6 Hz, 2H), 7.6-7.55 (m, 3H), 7.07 (d, J = 9.2 Hz, 2H),3.77 (t, J = 4.9 Hz, 4H), 3.15 (t, J = 4.6 Hz, 4H) 401.3 (M + 1) 2

13.47 (s, 1H), 11.62 (s, 1H), 9.75 (br, 2H), 8.51 (d, J = 8.3 Hz, 2H),8.37 (s, 1H), 8.13 (d, J = 8.3 Hz, 2H), 8.0 (d, J = 8.3 Hz, 2H), 7.76(d, J = 8.3 HZ, 2H), 4.4 (s, 2H), 3.91 (s, 3H), 3.57-3.51 (m, 8H) 472.1(M + 1) 3

12.9 (s, 1H), 11.52 (s, 1H), 9.4 (s, 2H), 7.94 (s, 1H), 7.81 (d, J = 7.0Hz, 2H), 7.61 (br, 2H), 4.3 (br, 2H), 3.84 (m, 4H), 3.7 (m, 4H), 3.47(m, 8H) 423.0 (M + 1) 4

13.37 (s, 1H), 11.51 (s, 1H), 8.45 (d, J = 5.9 Hz, 2H), 8.39 (s, 1H),7.89 (d, J = 8.1 Hz, 2H), 7.6 (d, J = 7.0 Hz, 3H), 7.44 (d, J = 8.6 Hz,2H), 4.03 (s, 4H), 3.59-3.58 (m, 4H), 3.5 (s, 2H) 415.4 (M + 1) 5

13.31 (s, 1H), 11.33 (s, 1H), 8.42 (d, J = 6.7 Hz, 2H), 8.3 (s, 1H),7.75 (d, J = 8.9 Hz, 2H), 7.62-7.56 (m, 3H), 7.06 (d, J = 8.9 Hz, 2H),3.18 (t, J = 4.4 Hz, 4H), 2.39 (q, J = 7.2 Hz, 2), 1.24 (m, 4H), 1.05(t, J = 7.2 Hz, 3H) 428.2 (M + 1) 6

13.37 (s, 2H), 11.5 (s, 1H), 8.44 (d, J = 5.9 Hz, 2H), 8.34 (s, 1H),7.87 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 7.0 Hz, 3H), 7.41 (d, J = 8.3 Hz,2H), 3.48 (s, 2H), 2.40-2.31 (m, 10H), 0.98 (t, J = 7.1 Hz, 3H) 442.3(M + 1) 7

13.42 (s, 1H), 11.62 (s, 1H), 8.45 (d, J = 6.8 Hz, 2H), 8.37 (s, 1H),8.03 (d, J = 7.3 Hz, 2H), 7.69-7.58 (m, 5H), 3.43 (m, 10H) 414.0 (M + 1)8

11.68 (s, 1H), 8.42 (d, J = 6.2 Hz, 2H), 8.30 (s 1H), 7.75 (d, J = 8.9Hz, 2H), 7.57 (d, J = 8.9 Hz, 2H), 7.04 (d, J = 8.9 Hz, 2H), 3.08-3.07(m, 4H), 2.86-2.85 (m, 4H) 400.3 (M + 1) 9

13.42 (s, 1H), 11.63 (s, 1H), 8.47- 8.45 (m, 2H), 8.37 (s, 1H), 8.01 (d,J = 8.3 Hz, 2H), 7.63-7.57 (m, 5H), 3.63-3.55 (m, 8H) 429.2 (M + 1) 10

13.28 (s, 1H), 11.23 (s, 1H), 8.42- 8.4 (d, J = 9.2 Hz, 2H), 8.27 (s,1H), 7.66 (d, J = 9.2 Hz, 2H), 7.59-7.55 (m, 3H), 6.80 (d, J = 8.8 Hz,2H), 4.77 (t, J = 5.4 Hz, 2H), 3.58 (dd, J = 5.9 Hz, 11.7 Hz, 4H),3.47-3.44 (m, 4H) 419.3 (M + 1) 11

13.34 (s, 1H), 11.35 (s, 1H), 8.45- 8.42 (m, 2H), 8.3 (s, 1H), 8.11 (s,2H), 7.80 (d, J = 8.8 Hz, 2H), 7.61-7.56 (m, 3H), 7.15 (d, J = 7.3 Hz,2H), 3.7 (m, 2H), 3.27-3.22 (m, 4H) 457.2 (M + 1) 12

13.32 (s, 1H), 11.31 (s, 1H), 8.42 (d, J = 7.0 Hz, 2H), 8.3 (s, 1H),7.76 (d, J = 9.2 Hz, 2H), 7.62-7.55 (m, 3H), 7.07 (d, J = 9.2 Hz, 2H),3.35-3.29 (m, 8H), 2.79 (s, 2H) 458.1 (M + 1) 13

13.31 (s, 1H), 12.3 (s, 1H), 11.31 (s, 1H), 8.43-8.41 (m, 2H), 8.3 (s,1H), 7.74 (d, J = 9.3 Hz, 2H), 7.6- 7.55 (m, 3H), 7.07 (d, J = 8.8 Hz,2H), 3.69-3.66 (m, 2H), 2.79 (t, J = 10.8 Hz, 2H), 2.43-2.39 (m, 1H),1.94-1.91 (m, 2H), 1.72-1.66 (m, 2H) 443.0 (M + 1) 14

11.5 (s, 1H), 8.42-8.41 (m, 2H), 8.31 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H),7.57 (d, J = 7.4 Hz, 3H), 7.09 (d, J = 9.3 Hz, 2H), 3.39 (m, 4H), 3.17(m, 8H) 457.3 (M + 1) 15

13.1 (s, 1H), 11.6 (s, 1H), 8.45 (d, J = 6.4 Hz, 2H), 8.36 (s, 1H), 7.97(d, J = 7.4 Hz, 2H), 7.59 (m, 3H), 7.53 (d, J = 7.9 Hz, 2H), 3.36 (br,2H), 2.99 (s, 3H), 2.2-2.0 (m, 6H), 1.85 (s, 2H) 444.4 (M + 1) 16

13.31 (s, 1H), 11.31 (s, 1H), 8.42 (dd, J = 1.4, 7.8 Hz, 2H) 8.31 (d, J= 9.2 Hz, 2H), 7.74 (d, J = 9.2 Hz, 2H), 7.61-7.57 (m, 3H), 7.09 (d, J =9.2 Hz, 2H), 3.22-3.2 (m, 4H), 2.66-2.65 (m, 2H), 1.84-1.78 (m, 24H)454.1 (M + 1) 17

13.31 (s, 1H), 11.29 (s, 1H), 8.43- 8.40 (m, 2H), 8.29 (s, 1H), 7.73 (d,J = 8.7 Hz, 2H), 7.6-7.64 (m, 3H), 7.07 (d, J = 9.2 Hz, 2H), 4.36 (s,4H), 3.13 (t, J = 5.4 Hz, 4H), 1.91 (t, J = 5.4 Hz, 4H) 441.4 (M + 1) 18

12.73 (s, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.58 (d, J = 8.7 Hz, 2H),6.97 (d, J = 9.2 Hz, 2H), 3.89 (br, 4H), 3.73 (t, J = 4.9 Hz, 4H), 3.09(t, J = 4.9 Hz, 4H), 1.4 (d, J = 4.6 Hz, 4H), 0.38 (s, 4H) 434.0 (M + 1)19

13.3 (s, 1H), 12.02 (s, 1H), 11.30 (s, 1H), 8.42 (d, J = 6.7 Hz, 2H),8.28 (s, 1H), 7.73 (d, J = 8.9 Hz, 2H), 7.6-7.55 (m, 3H), 7.07 (d, J =9.2 Hz, 2H), 3.28-3.27 (m, 2H), 3.1-3.05 (m, 1H), 2.5 (t, J = 1.6 Hz,2H), 1.8-1.5 (m, 4H), 0.99- 0.96 (m, 2H) 469.3 (M + 1) 20

13.31 (s, 1H), 11.31 (s, 1H), 8.43- 8.41 (m, 2H), 8.39 (s, 1H), 7.74 (d,J = 8.8 Hz, 2H), 7.62-7.54 (m, 3H), 7.08 (d, J = 9.3 Hz, 2H), 4.11-4.06(m, 2H), 3.26-3.19 (m, 2H), 3.07-3.02 (m, 1H), 2.42 (t, J = 2.0 Hz, 2H),1.84-1.5 (m, 4H), 1.19 (t, J = 7.1 Hz, 3H), 1.06-1.02 (m, 2H) 497.0(M + 1) 21

13.4 (s, 1H), 11.55 (s, 1H), 8.45 (d, J = 7.8 Hz, 2H), 8.35 (s, 1H),7.93 (d, J = 7.8 Hz, 2H), 7.63-7.58 (m, 3H), 7.5 (d, J = 8.3 Hz, 2H),1.75 (m, 2H), 1.54-1.50 (m, 2H), 0.93 (m, 2H) 483.0 (M + 1) 22

8.47 (s, 1H), 8.39 (dd, J = 3.2, 6.6 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H),7.58-7.57 (m, 3H), 7.08 (d, J = 9.3 Hz, 2H), 3.14 (t, J = 5.4 Hz, 2H),2.56 (t, J = 2.0 Hz, 2H), 1.86-1.76 (m, 2H), 1.69-1.47 (m, 2H), 1.34-1.31 (m, 1H), 0.85-0.83 (m, 1H), 0.55-0.52 (m, 1H)   469 (M + 1) 23

13.39 (s, 1H), 11.5 (s, 1H), 8.44 (d, J = 6.3 Hz, 2H), 8.34 (s, 1H),7.86 (t, J = 8.1 Hz, 2H), 7.62 (d, J = 7.4 Hz, 2H), 7.48 (d, J = 6.8 Hz,1H), 7.40 (d, J = 6.9 Hz, 2H), 4.27 (s, 4H), 3.44 (s, 2H), 2.33-2.28 (m,4H), 1.76 (m, 4H) 455.0 (M + 1) 24

13.39 (s, 1H), 11.61 (s, 1H), 9.61 (br 2H), 8.52 (d, J = 1.9 Hz, 1H),8.31 (s, 1H), 8.02 (d, J = 9.3 Hz, 2H), 7.85-7.84 (m, 1H), 7.75-7.72 (m,3H), 4.40 (s, 2H), 3.49-3.42 (m, 4H), 2.50 (t, J = 2.0 Hz, 4H)   420(M + 1) 25

12.86 (s, 1H), 11.51 (s, 1H), 9.67 (s, 2H), 7.95 (s, 1H), 7.82 (d, J =7.8 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 4.36 (br, 2H), 4.12-3.92 (m, 4H),3.5-3.37 (m, 5H), 3.35-3.23 (m, 2H), 1.74-1.52 (m, 6H), 1.06- 1.02 (m,2H) 491.3 (M + 1) 26

12.8 (s, 1H), 11.17 (s, 1H), 7.88 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H),6.96 (d, J = 8.8 Hz, 2H), 3.8 (m, 4H), 3.67 (m, 4H), 3.29 (m, 4H),3.13-3.11 (m, 4H), 2.37-2.35 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H) 437.3(M + 1) 27

13.48 (s, 1H), 11.64 (s, 1H), 9.42 (br, 2H), 8.53 (d, J = 8.3 Hz, 2H),8.4 (s, 1H), 8.14 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 7.8 Hz, 2H), 7.73(br, 2H), 4.40 (br, 2H), 3.63 (m, 4H), 3.51-3.39 (m, 4H) 458.0 (M + 1)28

13.36 (s, 1H), 11.33 (s, 1H), 8.51 (d, J = 8.8 Hz, 2H), 8.31 (s, 1H),7.73 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.06 (d, J = 9.3 Hz,2H), 3.30 (m, 4H), 3.19-3.16 (m, 4H), 2.39-2.33 (m, 4H), 1.05 (t, J =7.1 Hz, 3H) 512.2 (M + 1) 29

13.4 (br, 1H), 11.6 (br, 1H), 8.52 (d, J = 8.3 Hz, 2H), 8.33 (s, 1H),8.14 (d, J = 8.3 Hz, 2J), 7.77 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz,2H), 3.91 (s, 3H), 3.77 (t, J = 4.7 Hz, 4H), 3.15 (t, J = 4.7 Hz, 4H)459.2 (M + 1) 30

12.87 (s, 1H), 11.51 (s, 1H), 9.8 (br, 2H), 7.96 (s, 1H), 7.82 (d, J =7.8 Hz, 2H), 6.68 (d, J = 8.3 Hz, 2H), 4.82 (m, 6H), 4.38 (s, 2H), 3.86(m, 4H), 3.48 (m, 4H), 1.66 (m, 2H), 1.09 (m, 2H) 421.1 (M + 1) 31

13.43 (s, 1H), 11.59 (s, 1H), 9.47 (br, 2H), 8.37 (s, 1H), 8.05-8.03 (m,3H), 7.98 (s, 1H), 7.74 (d, J = 7.8 Hz, 2H), 7.51 (t, J = 8.1 Hz, 1H),7.2 (dd, J = 4.0, 8.3 Hz, 1H), 4.41 (br, 2H), 3.89 (s, 3H), 3.45 (t, J =4.9 Hz, 4H), 3.23 (m, 4H) 443.9 (M + 1) 32

12.99 (s, 1H), 11.53 (s, 1H), 9.6 (br, 2H), 9.35 (br, 2H), 7.98 (s, 1H),7.9 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 7.8 Hz, 2H), 4.36 (br, 2H), 4.08(m, 4H), 3.44 (m, 4H), 3.39 (m, 8H) 422.2 (M + 1) 33

13.37 (s, 1H), 11.59 (s, 1H), 9.4 (br, 2H), 8.32 (s, 1H), 8.09 (dd, J =1.5, 8.5 Hz, 1H), 8.0 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 1.5 Hz, 1H),7.71 (d, J = 6.4 Hz, 2H), 7.12 (d, J = 8.3 Hz, 1H), 6.17 (s, 2H), 4.4(br, 2H), 3.65-3.49 (m, 4H), 2.51- 2.5 (m, 4H) 458.1 (M + 1) 34

13.2 (s, 1H), 11.29 (s, 1H), 8.42- 8.4 (m, 2H), 8.28 (s, 1H), 7.72 (d, J= 9.3 Hz, 2H), 7.6-7.54 (m, 3H), 7.04 (d, J = 8.8 Hz, 2H), 3.72-3.69 (m,2H), 2.71-2.66 (m, 2H), 2.47- 2.41 (m, 1H), 2.2-2.18 (m, 2H), 1.84-1.76(m, 2H), 1.35-1.27 (m, 2H)   455 (M − 1) 35

13.37 (s, 1H), 11.51 (s, 1H), 8.45- 8.43 (m, 2H), 8.33 (s, 1H), 7.89 (d,J = 8.3 Hz, 2H), 7.62-7.56 (m, 3H), 7.44 (d, J = 8.3 Hz, 2H), 3.58 (m,2H), 2.85 (m, 2H), 2.49-2.14 (m, 3H), 1.84-1.81 (m, 2H), 1.64- 1.59 (m,2H)   457 (M + 1) 36

13.42 (s, 1H), 11.56 (s, 1H), 9.63 (br, 2H), 8.34 (s, 1H), 8.10 (d, J =8.8 Hz, 2H), 7.84 (dd, J = 1.7, 7.6 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H),5.56-7.52 (m, 1H), 7.26 (d, J = 8.3 Hz, 2H), 7.10 (t, J = 7.1 Hz, 1H),4.39 (s, 2H), 3.94 (s, 3H), 3.64 (m, 4H), 3.47-3.37 (m, 4H) 444.1(M + 1) 37

13.28 (s, 1H), 11.30 (s, 1H), 8.46 (d, J = 1.9 Hz, 1H), 8.24 (s, 1H),7.81-7.80 (m, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.69 (dd, J = 3.2, 5.2 Hz,1H), 7.05 (d, J = 8.8 Hz, 2H), 3.32-3.3 (m, 8H), 2.39-2.33 (m, 2H), 1.05(t, J = 7.3 Hz, 3H) 434.0 (M + 1) 38

13.11 (b, 1H), 12.87 (s, 1H), 11.56 (s, 1h), 9.61 (b, 2H), 7.95 (s, 1h),7.88 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 5.05 (s, 2H), 3.89(m, 4H), 3.54 (m, 4H), 3.01 (s, 4H), 2.75 (m, 4H), 1.60 (m, 4H) 475.0(M + 1) 39

12.0 (br, 1H), 8.46-8.45 (m, 1H), 8.23 (s, 1H), 7.81 (dd, J = 1.0, 4.9Hz, 1H), 7.74 (d, J = 9.3 Hz, 2H), 7.69 (dd, J = 3.0, 4.9 Hz, 1H), 7.07(d, J = 9.3 Hz, 2H), 3.27-3.2 (m, 2H), 3.19-3.08 (m, 1H), 2.61- 2.53 (m,2H), 1.81-1.77 (m, 2H), 1.60-1.55 (m, 2H), 1.01-0.95 (m, 2H) 475.0(M + 1) 40

13.44 (s, 1H), 11.62 (s, 1H), 9.5 (b, 2H), 8.42 (d, J = 8.8 Hz, 2H),8.35 (s, 1H), 7.98 (d, J = 7.8 Hz, 2H), 7.71 (b, 2H), 7.66 (d, J = 8.3Hz, 2H), 4.4 (b, 2H), 3.95 (m, 4H), 3.41 (m, 4H) 448.0 (M + 1) 41

13.36 (s, 1H), 11.60 (s, 1H), 9.68 (b, 2H), 8.40 (d, J = 8.8 Hz, 2H),8.31 (s, 1H), 8.01 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 8.8 Hz, 2H), 7.13(d, J = 8.8 Hz, 2H), 4.41 (s, 2H), 3.87-3.75 (m, 7H), 3.49-3.45 (m, 4H)444.0 (M + 1) 42

12.80 (s, 1H), 11.95 (br, 1H), 11.17 (s, 1H), 7.88 (s, 1H), 7.55 (d, J =8.8 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 3.81 (m, 4H), 3.67 (m, 4H),3.23-3.16 (m, 4H), 3.06- 3.03 (m, 1H), 1.77-1.76 (m, 2H), 1.56-1.53 (m,2H), 0.98-0.94 (m, 2H)   478 (M + 1) 43

12.84 (s, 1H), 11.95 (br, 1H), 11.49 (s, 1H), 9.62 (br, 2H), 7.93 (s,1H), 7.83 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 4.8-4.6 (m,2H), 4.36 (br, 2H), 3.65 (br, 4H), 3.46 (br, 4H), 3.1-4.04 (m, 1H),2.2-2.09 (m, 2H), 2.02 (br, 2H), 1.82-1.79 (m, 2H), 1.23-1.19 (m, 2H)  479 (M + 1) 44

12.93 (s, 1H), 11.41 (s, 1H), 8.72 (br, 2H), 7.98 (s, 1H), 7.75 (d, J =7.3 Hz, 2H), 7.43 (d, J = 7.3 Hz, 2H), 4.62-4.53 (m, 2H), 4.0-3.94 (m,2H), 3.82 (br, 2H), 3.19 (br, 4H), 2.95-2.83 (m, 8H)   455 (M + 1) 45

13.02 (s, 1H), 11.55 (s, 1H), 11.18 (br, 1H), 9.67 (br, 2H), 7.99 (s,1H), 7.81 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 7.4 Hz, 2H), 4.71 (br, 2H),4.39 (s, 2H), 3.36 (br, 6H), 3.30- 3.09 (m, 8H), 2.80 (s, 3H) 436.2 (M +1_ 46

11.23 (s, 1H), 8.34 (d, J = 8.8 Hz, 2H), 8.2 (s, 1H), 7.69 (d, J = 8.8Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 9.2 Hz, 2H), 3.85 (s,3H), 3.27-3.22 (m, 8H), 3.09-3.06 (m, 1H), 1.55-1.49 (m, 2H) 479.73 (M −1)  47

11.35 (s, 1H), 8.27 (s, 1H), 7.98 (d, J = 7.4 Hz, 2H), 7.93 (s, 1H),7.69 (d, J = 7.8 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 7.8 Hz,1H), 7.02 (d, J = 7.8 Hz, 2H), 3.84 (s, 3H), 3.11 (br peak, 5H), 1.85(br, 2H), 1.51-1.16 (m, 4H) 499.3 (M + 1) 48

12.86 (s, 1H), 11.57 (s, 1H), 9.42 (br, 2H), 7.96 (s, 1H), 7.94 (d, J =7.3 Hz, 2H), 7.61 (d, J = 6.9 Hz, 2H), 4.35 (br, 2H), 3.64-3.57 (m, 4H),3.46-3.38 (m, 4H), 3.26-3.23 (m, 4H), 1.99 (m, 4H) 407.5 (M + 1) 49

12.84 (s, 1H), 11.53 (s, 1H), 7.94 (s, 1H), 7.90 (d, J = 7.9 Hz, 2H),7.62 (d, J = 6.9 Hz, 2H), 4.3 (br, 2H), 3.42 (m, 4H), 3.24 (s, 6H), 2.51(m, 4H) 381.3 (M + 1) 50

13.28 (s, 1H), 11.8 (br, 1H), 11.58 (s, 1H), 9.41 (br, 2H), 8.15 (s,1H), 7.9 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 7.8 Hz, 2H), 4.45 (q, J = 7.1Hz, 2H), 4.37 (br, 2H), 3.47 (m, 4H), 3.39 (m, 4H), 1.38 (t, J = 7.1 Hz,3H) 382.4 (M + 1) 51

12.87 (s, 1H), 11.50 (s, 1H), 9.60 (br, 2H), 7.95 (s, 1H), 7.83 (d, J =8.3 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 4.65-4.50 (m, 2H), 4.38 (s, 2H),2.64-2.59 (m, 1H), 1.97-1.94 (m, 2H), 1.6 (s, 2H), 1.56-1.54 (m, 2H)465.3 (M + 1) 52

12.84 (s, 1H), 11.54 (s, 1H), 9.56 (br, 2H), 7.95 (s, 1H), 7.88 (d, J =8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 4.37 (s, 2H), 3.84-3.79 (m, 8H),2.51-2.50 (m, 4H), 1.81-1.77 (m, 4H), 1.53 (s, 4H) 433.1 (M − 1) 53

13.29 (s, 1H), 11.95 (br, 1H), 11.26 (s, 1H), 8.25 (s, 1H), 7.78 (d, J =9.2 Hz, 2H), 7.74 (dd, J = 1.7 Hz, J = 7.6 Hz, 1H), 7.52-7.48 (m, 1H),7.2 (d, J = 7.8 Hz, 1H), 7.07 (t, J = 7.1 Hz, 1H), 6.99 (d, J = 9.3 Hz,2H), 3.88 (s, 3H), 3.27- 2.15 (m, 4H), 3.05-3.03 (m, 1H), 1.79-1.75 (m,2H), 1.58-1.50 (m, 2H), 0.98-0.92 (m, 2H) 499.3 (M + 1) 54

12.81 (s, 1H), 11.53 (s, 1H), 9.35 (br, 2H), 7.93 (s, 1H), 7.89 (d, J =8.3 Hz, 2H), 7.62 (d, J = 7.8 Hz, 2H), 4.33 (br, 2H), 3.7-3.66 (m, 6H),3.29 (m, 4H), 1.19-1.18 (m, 12H) 437.2 (M + 1) 55

13.4 (s, 1H), 11.58 (br, 1H), 9.70 (br, 2H), 8.45 (d, J = 8.3 Hz, 2H),8.34 (s, 1H), 8.01 (d, J = 8.3 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.76(d, J = 8.3 Hz, 2H), 4.45 (m, 4H), 3.94-3.65 (m, 4H), 3.5 (m, 4H),3.38-3.16 (m, 6H), 1.6 (s, 2H) 513.2 (M + 1) 56

12.80 (s, 1H), 11.95 (br, 1H), 11.50 (s, 1H), 9.62 (br, 2H), 7.95 (s,1H), 7.81 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.3 Hz, 2H), 4.37 (s. 2H),4.17 (br, 2H), 3.75-3.63 (m, 4H), 3.47 (br, 6H), 3.36-3.18 (m, 3H),1.79-1.76 (m, 2H) 446.3 (M + 1) 57

13.01 (s, 1H), 11.95 (br, 1H), 11.02 (s, 1H), 9.59 (br, 2H), 8.0 (s,1H), 7.81 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 7.8 Hz, 2H), 4.8 (br, 2H),4.37 (br, 2H), 3.65-3.61 (m, 8H), 3.39-3.04 (m, 8H), 1.29 (t, J = 7.4Hz, 3H) 450.4 (M + 1) 58

13.31 (s, 1H), 11.24 (s, 1H), 8.46- 8.44 (m, 2H), 8.34 (s, 1H), 8.3 (s,1H), 7.93 (s, 1H), 7.62-7.56 (m, 3H), 4.31 (t, J = 6.3 Hz, 2H), 3.54 (t,J = 4.4 Hz, 4H), 2.75 (t, J = 6.4 Hz, 2H), 2.5-2.44 (m, 4H) 419.2(M + 1) 59

12.95 (s, 1H), 11.53 (s, 1H), 9.65 (br, 2H), 9.28-9.22 (m, 2H), 7.97 (s,1H), 7.87-7.80 (m, 2H), 7.67 (d, J = 8.9 Hz, 2H), 4.37 (br, 2H),4.09-4.04 (m, 2H), 3.96-3.90 (m, 2H), 3.52-3.20 (m, 10H), 2.12- 2.09 (m,2H), 1.6 (s, 2H) 436.3 (M + 1) 60

12.70 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.64 (d, J = 9.3 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 3.81-3.76 (m, 4H), 3.75-3.72 (m, 4H), 3.09 (t,J = 4.7 Hz, 4H), 1.76 (t, J = 4.4 Hz, 4H), 1.51 (m, 4H) 422.3 (M + 1) 61

13.28 (s, 1H), 11.71 (s, 1H), 9.68 (br, 2H), 8.1 (s, 1H), 7.97 (d, J =7.8 Hz, 2H), 7.68 (d, J = 6.8 Hz, 2H), 4.37 (br, 2H) 368.3 (M + 1) 62

12.7 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 9.3 Hz, 2H),6.98 (d, J = 9.3 Hz, 2H), 3.81 (t, J = 5.9 Hz, 2H), 3.75 (t, J = 5.9 Hz,2H), 3.26-3.01 (m, 5H), 1.79-1.75 (m, 6H), 1.55-1.51 (m, 6H), 0.95- 0.92(m, 2H), 3.65 (s, 3H), 3.53- 3.29 (m, 10H) 490.4 (M + 1) 63

13.35 (s, 1H), 11.19 (s, 1H), 9.5 (br, 2H), 8.49-8.47 (m, 2H), 8.43 (s,1H), 8.32 (s, 1H), 8.06 (s, 1H), 7.63-7.60 (m, 3H), 4.68 (br, 2H),4.06-3.95 (m, 8H), 3.65 (m, 2H) 418.1 (M + 1) 64

13.31 (s, 1H), 11.14 (s, 1H), 8.46 (d, J = 6.4 Hz, 2H), 8.31 (d, J = 8.3Hz, 2H), 7.92 (s, 1H), 7.62- 7.58 (m, 3H), 4.29 (t, J = 6.1 Hz, 2H),2.74 (t, J = 6.2 Hz, 2H), 2.45 (m, 4H), 2.28 (m, 4H), 2.09 (s, 3H) 432.2(M + 1) 65

13.31 (s, 1H), 11.14 (s, 1H), 8.32 (d, J = 10.7 Hz, 2H), 7.92 (s, 1H),7.64-7.54 (m, 3H), 4.29 (t, J = 6.4 Hz, 2H), 2.74 (t, J = 6.4 Hz, 2H),2.45-2.31 (m, 8H), 2.23 (q, J = 7.1 Hz, 2H) 446.1 (M + 1) 66

12.75 (s, 1H), 12.0 (br, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.56 (d, J =9.3 Hz, 2H), 7.0 (d, J = 8.8 Hz, 2H), 4.72 (br, 2H), 3.27-3.14 (m, 4H),3.06-2.96 (m, 4H), 1.97-1.91 (m, 1H), 1.84-1.75 (m, 4H), 1.60- 1.52 (m,2H), 1.34-1.17 (m, 3H), 0.99-0.94 (m, 2H) 515.6 (M + 1) 67

12.76 (s, 1H), 11.40 (s, 1H), 7.89 (s, 1H), 7.22 (s, 2H), 3.81 (m, 10H),3.65 (s, 3H), 1.75 (m, 4H), 1.51 (m, 4H) 427.3 (M + 1) 68

12.79 (s, 1H), 11.51 (s, 1H), 7.91 (s, 1H), 7.85 (d, J = 8.3 Hz, 2H),7.47 (d, J = 8.4 Hz, 2H), 3.84-3.77 (m, 4H), 3.61 (m, 4H), 3.51 (m, 4H),1.81-1.76 (m, 4H), 1.52 (m, 4H) 450.3 (M + 1) 69

12.7 (s, 1H), 12.1 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H), 6.95(d, J = 9.3 Hz, 2H), 3.8 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H),3.66-3.63 (m, 2H), 2.63 (m, 3H), 2.19 (d, J = 6.8 Hz, 2H), 1.77-1.74 (m,6H), 1.51 (m, 4H), 1.4-1.2 (m, 2H) 478.3 (M + 1) 70

12.80 (s, 1H), 12.10 (br, 1H), 11.15 (s, 1H), 7.89 (s, 1H), 7.55 (d, J =8.3 Hz, 2H), 6.97 (s, 1H), 3.88 (m, 4H), 3.67 (s, 2H), 3.65- 3.64 (m,2H), 2.68-2.62 (m, 2H), 2.55 (m, 4H), 2.19 (d, J = 6.4 Hz, 2H), 1.99 (m,1H), 1.77-1.75 (m, 2H), 1.34 (t, J = 7.8 Hz, 4H) 504.3 (M + 1) 71

12.75 (s, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 9.3 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 4.72 (m, 2H), 3.66 (d, J = 11.7 Hz, 2H),3.02-2.95 (m, 2H), 2.19 (d, J = 6.8 Hz, 2H), 2.00-1.97 (m, 1H), 1.84-1.74 (m, 5H), 1.34-1.21 (m, 4H) 503.4 (M + 1) 72

12.95 (s, 1H), 11.51 (s, 1H), 9.33- 9.29 (m, 2H), 7.98 (s, 1H), 7.9-7.85 (m, 4H), 4.09-4.04 (m, 6H), 3.55 (m, 4H), 3.32-3.17 (m, 6H),2.2-2.11 (m, 4H), 1.73-1.70 (m, 1H), 1.24-1.05 (m, 4H) 491.1 (M + 1) 73

12.8 (s, 1H), 12.05 (br, 1H), 11.16 (s, 1H), 7.89 (s, 1H), 7.56 (d, J =8.8 Hz, 2H), 7.01 (d, J = 7.9 Hz, 2H), 3.87-3.81 (m, 6H), 3.27-3.16 (m,4H), 3.04-3.03 (m, 2H), 1.82- 1.77 (m, 4H), 1.57-1.53 (m, 4H), 0.98-0.96(m, 2H) 516.3 (M + 1) 74

12.79 (s, 1H), 12.06 (s, 1H), 11.14 (s, 1H), 7.89 (s, 1H), 7.55 (d, J =8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 4.14 (m, 2H), 3.64-3.59 (m, 2H),3.27-3.16 (m, 4H), 3.07-3.02 (m, 1H), 2.01-1.91 (m, 2H), 1.82- 1.73 (m,4H), 1.61-1.52 (m, 4H), 0.99-0.93 (m, 2H) 501.4 (M + 1) 75

12.79 (s, 1H), 12.05 (s, 1H), 11.13 (s, 1H), 7.89 (s, 1H), 7.54 (d, J =8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.15 (m, 2H), 3.67-3.59 (m, 4H),3.2-3.16 (m, 2H), 2.65 (t, J = 11.8 Hz, 2H), 2.20 (d, J = 6.9 Hz, 2H),1.95 (m, 2H), 1.78-1.75 (m, 5H), 1.31-1.24 (m, 2H) 489.2 (M + 1) 76

12.84 (s, 1H), 12.05 (s, 1H), 11.35 (s, 1H), 7.91 (s, 1H), 7.66 (d, J =8.8 Hz, 2H), 7.32 (d, J = 8.8 Hz, 2H), 4.16 (br, 2H), 3.42 (s, 2H),3.22-3.17 (m, 2H), 2.75 (d, J = 11.3 Hz, 2H), 2.44 (t, J = 3.9 Hz, 1H),2.18-2.15 (m, 1H), 1.99-1.95 (m, 4H), 1.79-1.76 (m, 4H), 1.58- 1.50 (m,2H) 489.3 (M + 1) 77

12.76 (s, 1H), 12.0 (s, 1H), 11.39 (s, 1H), 7.90 (s, 1H), 7.76 (d, J =7.4 Hz, 2H), 7.34 (m, 2H), 3.82- 3.78 (m, 4H), 2.86 (m, 2H), 2.14 (m,2H), 1.99 (m, 1H), 1.76-1.68 (m, 8H), 1.52 (m, 4H), 1.24-1.18 (m, 4H)492.4 (M + 1) 78

¹ 12.81 (s, 1H), 12.0 (s, 1H), 11.39 (s, 1H), 7.91 (s, 1H), 7.72 (d, J =7.3 Hz, 2H), 7.38 (d, J = 6.9 Hz, 2H), 4.8-4.71 (m, 2H), 3.65 (br, 2H),3.02-2.90 (m, 4H), 2.33-2.29 (m, 4H), 2.01 (m, 2H), 1.86-1.83 (m, 4H),1.62 (m, 2H), 1.23 (m, 2H) 503.3 (M + 1) 79

13.23 (s, 1H), 12.09 (s, 1H), 11.21 (s, 1H), 8.16 (s, 1H), 7.68 (d, J =8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.32-3.21 (m, 2H), 3.06 (m, 1H),2.77-2.63 (m, 1H), 1.97 (m, 2H), 1.78-1.67 (m, 5H), 1.59-1.54 (m, 5H),1.42-1.23 (m, 4H), 0.98- 0.95 (m, 2H) 475.4 (M + 1) 80

12.7 (s, 1H), 11.61 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 9.2 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 3.81- 3.67 (m, 6H), 2.69-2.54 (m, 4H),1.80-1.74 (m, 7H), 1.51 (m, 4H), 1.43-1.36 (m, 2H) 459.3 (M + 1) 81

13.23 (s, 1H), 12.05 (brs, 1H), 11.20 (s, 1H), 8.16 (s, 1H), 7.69 (d, J= 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.26-3.20 (m, 4H), 3.19-3.13(m, 1H), 2.93-2.90 (m, 1H), 2.02-1.91 (m, 2H), 1.82-1.76 (m, 6H),1.63-1.52 (m, 9H), 0.99- 0.97 (m, 2H) 489.4 (M + 1) 82

13.31 (s, 1H), 11.31 (s, 1H), 8.43- 8.41 (m, 2H), 8.29 (s, 1H), 7.74 (d,J = 9.3 Hz, 2H), 7.76-7.54 (m, 3H), 7.07 (d, J = 8.8 Hz, 2H), 3.76 (m,2H), 2.72 (m, 2H), 2.57 (d, J = 6.3 Hz, 2H), 1.83-1.80 (m, 3H),1.45-1.42 (m, 2H) 438.4 (M + 1) 83

13.37 (s, 1H), 11.51 (s, 1H), 8.44 (dd, J = 1.7 Hz, 7.6 Hz, 2H), 8.33(s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.62-7.57 (m, 3H), 7.44 (d, J = 8.3Hz, 2H), 5.37 (s, 1H), 3.9 (br, 1H), 3.52 (m, 4H), 2.39 (m, 4H), 1.30(s, 6H) 500.3 (M + 1) 84

12.75 (s, 1H), 11.38 (s, 1H), 7.90 (s, 1H), 7.75 (d, J = 8.3 Hz, 2H),7.33 (d, J = 7.9 Hz, 2H), 5.37 (s, 1H), 3.83-3.76 (m, 4H), 3.38 (s, 2H),3.13-3.08 (m, 4H), 2.36 (m, 4H), 1.8-1.76 (m, 4H), 1.52 (m, 4H), 1.29(s, 6H) 521.4 (M + 1) 85

12.74 (s, 1H), 11.35 (s, 1H), 7.89 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H),7.30 (d, J = 7.8 Hz, 2H), 4.12-4.11 (m, 4H), 3.81-3.77 (m, 6H), 2.35 (m,4H), 2.16 (s, 1H), 1.85-1.75 (m, 4H), 1.51 (m, 4H) 449.3 (M + 1) 86

13.35 (s, 1H), 11.48 (s, 1H), 8.45- 8.30 (m, 2H), 8.28 (s, 1H), 7.86 (d,J = 8.3 Hz, 2H), 7.59-7.57 (m, 3H), 7.38 (d, J = 7.8 Hz, 2H), 3.50 (m,6H), 2.73-2.68 (m, 2H), 1.91- 1.90 (m, 3H) 457.3 (M + 1) 87

13.21 (s, 1H), 11.45 (s, 1H), 8.43- 8.31 (m, 2H), 8.30 (s, 1H), 7.82-7.79 (m, 2H), 7.60-7.56 (m, 3H), 7.39-7.33 (m, 2H), 3.31 (s, 1H), 2.67(m, 1H), 2.36 (m, 1H), 2.14 (d, J = 6.8 Hz, 2H), 1.85 (m, 2H), 1.64 (m,4H), 1.48 (m, 1H) 454.2 (M − 1) 88

12.69 (s, 1H), 12.01 (s, 1H), 11.15 (s, 1H), 7.85 (s, 1H), 7.60 (d, J =8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 3.70 (m, 6H), 2.67 (m, 2H), 2.18(d, J = 5.8 Hz, 2H), 1.79 (m, 7H), 1.21-1.51 (m, 8H) 492.3 (M + 1) 89

12.89 (s, 1H), 1H), 12.28 (s, 1H), 1H), 11.30 (s, 1H), 9.78 (s, 2H),8.02 (s, 1H), 7.73 (d, J = 9.2 Hz, 2H), 7.06 (d, J = 9.2 Hz, 2H), 4.43(t, J = 4.8 Hz, 2H), 3.82 (t, J = 6 Hz, 2H), 3.75 (t, J = 6 Hz, 2H),3.64-3.37 (m, 10H), 1.77 (m, 4H), 1.59 (m, 4H) 464.7 (M + 1) 90

13.02 (s, 1H), 11.19 (s, 1H), 8.15 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 3.67 (d, J = 6.4 Hz, 2H), 2.92 (m, 1H), 2.65(m, 2H), 2.18 (d, J = 6.4 Hz, 2H), 2.08 (m, 2H), 1.99-1.54 (m, 14H),1.33-1.28 (m, 2H) 477.2 (M + 1) 91

12.73 (s, 1H), 12.01 (s, 1H), 11.32 (s, 1H), 7.88 (s, 1H), 7.68 (m, 2H),7.27 (m, 2H), 3.77 (m, 4H), 2.37 (m, 1H), 2.15 (d, J = 6.8 Hz, 2H),1.80-1.60 (m, 9H), 1.57 (m, 4H), 1.51 (m, 4H) 477.3 (M + 1) 92

12.71 (s, 1H), 11.16 (s, 1H), 7.85 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H),6.94 (d, J = 8.8 Hz, 2H), 3.96 (t, J = 6 Hz, 2H), 3.79 (t, J = 6 Hz,2H), 3.72 (t, J = 6 Hz, 2H), 2.35 (t, J = 7.2 Hz, 2H), 1.92 (m, 2H),1.74 (m, 4H), 1.50 (m, 4H) 439.1 (M + 1) 93

12.71 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H),6.96 (d, J = 8.8 Hz, 2H), 4.08 (t, J = 5.4 Hz, 2H), 3.79 (t, J = 6.4 Hz,2H), 3.73 (t, J = 6 Hz, 2H), 3.57 (t, J = 4.4 Hz, 4H), 2.68 (t, J = 5.4Hz, 2H), 2.50 (m, 4H), 1.75 (m, 4H), 1.50 (m, 4H)   466 (M + 1) 94

13.32 (s, 1H), 11.30 (s, 1H), 8.40 (d, J = 6.0 Hz, 2H), 8.30 (s, 1H),7.78 (d, J = 7.2 Hz, 2H), 7.55 (m, 3H), 7.08 (d, J = 7.2 Hz, 2H), 4.13(t, J = 5.4 Hz, 2H), 3.57 (t, J = 4.4 Hz, 4H), 2.68 (t, J = 5.4 Hz, 2H),2.50 (m, 4H) 445.1 (M + 1) 95

12.71 (s, 1H), 11.18 (s, 1H), 7.87 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H),6.97 (d, J = 8.4 Hz, 2H), 4.09 (t, J = 5.4 Hz, 2H), 3.80-3.74 (m, 4H),2.68 (t, J = 5.4 Hz, 2H), 2.62 (s, 3H), 2.50 (m, 8H), 1.74 (m, 4H), 1.50(m, 4H)   479 (M + 1) 96

12.71 (s, 1H), 12.01 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.67 (d, J =8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.08 (t, J = 5.4 Hz, 2H),3.79-3.74 (m, 4H), 2.96 (m, 2H), 2.75 (m, 2H), 2.13 (m, 4H), 1.75- 1.65(m, 11H), 1.20 (m, 2H) 522.1 (M + 1) 97

12.70 (s, 1H), 10.98 (s, 1H), 8.44 (d, J = 2.8 Hz, 1H), 7.95 (dd, J¹ =9.6 Hz, J² = 2.8 Hz, 1H), 7.86 (s, 1H), 6.90 (d, J = 9.6 Hz, 1H), 4.3(d, J = 13.2 Hz, 2H), 3.79 (t, J = 6.4 Hz, 2H), 3.70 (t, J = 6.0 Hz,2H), 2.8 (m, 2H), 2.50 (m, 2H), 1.88 (m, 1H), 1.87-1.74 (m, 6H),1.50-1.29 (m, 4H), 1.23 (m, 2H) 460.1 (M + 1) 98

12.71 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 4.07 (t, J = 5.2 Hz, 2H), 3.80 (t, J = 5.6 Hz,2H), 3.73 (t, J = 5.6 Hz, 2H), 2.87 (m, 2H), 2.45 (m, 2H), 2.19 (m, 3H),1.80-1.77 (m, 6H), 1.59 (m, 6H) 508.4 (M + 1) 99

12.70 (s, 1H), 10.97 (s, 1H), 8.43 (d, J = 2.8 Hz, 1H), 7.92 (dd, J¹ =9.6 Hz, J² = 2.8 Hz, 1H), 7.86 (s, 1H), 7.26 (s, br, 1H), 6.87 (d, J =9.6 Hz, 1H), 6.75 (s, br, 1H), 4.22 (d, J = 13.2 Hz, 2H), 3.79 (t, J =6.4 Hz, 2H), 3.70 (t, J = 6.0 Hz, 2H), 2.79 (m, 2H), 2.00 (d, J = 6.8Hz, 2H), 1.91 (m, 1H), 1.89-168 (m, 6H), 1.50-1.19 (m, 4H), 1.15 (m, 2H)  478 (M + 1) 100

12.75 (s, 1H), 12.01 (s, br, 1H), 11.12 (s, 1H), 7.87 (s, 1H), 7.56 (d,J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.89 (m, 2H), 3.65 (m, 2H),2.9 (m, 2H), 2.64 (m, 2H), 2.18 (d, J = 6.0 Hz, 2H), 1.92-1.74 (m, 7H),1.30 (s, 6H), 1.23 (m, 3H) 531.1 (M + 1) 101

13.31 (s, 1H), 11.11 (s, 1H), 8.55 (d, J = 2.8 Hz, 1H), 8.36 (m, 2H),8.29 (s, 1H), 8.04 (dd, J¹ = 9.2 Hz, J² = 2.8 Hz, 1H), 7.55 (m, 3H),6.98 (d, J = 9.2 Hz, 1H), 4.35 (d, J = 12.8 Hz, 2H), 2.85 (t, J = 11.2Hz, 2H), 2.50 (m, 2H), 1.90 (m, 1H), 1.89 (m, 2H), 1.27 (m, 2H) 439.1(M + 1) 102

13.31 (s, 1H), 11.11 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.36 (d, J = 6.8Hz, 2H), 8.30 (s, 1H), 8.04 (dd, J¹ = 9.2 Hz, J² = 2.4 Hz, 1H), 7.57 (m,3H), 7.27 (s, br, 1H), 6.97 (d, J = 9.2 Hz, 1H), 6.76 (s, br, 1H), 4.30(d, J = 12.8 Hz, 2H), 2.83 (t, J = 12.4 Hz, 2H), 2.02 (d, J = 7.2 Hz,2H), 1.74 (m, 3H), 1.19 (m, 2H) 457.2 (M + 1) 103

12.75 (s, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H),6.98 (d, J = 8.8 Hz, 2H), 4.89 (m, 2H), 3.7 (d, J = 12.8 Hz, 2H), 2.98(t, J = 11.2 Hz, 2H), 2.69-2.60 (m, 8H), 1.97-1.80 (m, 6H), 1.39 (m, 2H)484.3 (M + 1) 104

12.83 (s, 1H), 11.55 (s, 1H), 9.32 (s, br, 2H), 7.95 (s, 1H), 7.87 (d, J= 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 3.84-3.73 (m, 8H), 3.15 (m,4H), 1.81-1.76 (m, 4H), 1.52- 1.23 (m, 4H) 449.2 (M + 1) 105

12.69 (s, 1H), 11.14 (s, 1H), 7.85 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H),7.27 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.75 (s, 1H), 3.79-3.74 (m, 4H),3.63 (d, J = 11.6 Hz, 2H), 2.62 (t, J = 12.0 Hz, 2H), 2.02 (d, J = 6.8Hz, 2H), 1.76-1.71 (m, 7H), 1.50 (m, 4H), 1.30 (m, 2H) 477.5 (M + 1) 106

12.72 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 4.07 (s, br, 2H), 3.80 (s, br, 2H), 3.73 (s,br, 2H), 2.71-2.57 (m, 6H), 2.50- 2.32 (m, 6H), 1.99-1.62 (m, 4H),1.50-1.32 (m, 4H) 523.3 (M + 1) 107

12.69 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 4.06 (t, J = 5.6 Hz, 2H), 3.80 (t, J = 6.0 Hz,2H), 3.73 (t, J = 6.0 Hz, 2H), 2.69-2.63 m, 6H), 2.39 (m, 4H), 1.98 (m,4H), 1.50 (m, 4H) 465.2 (M + 1) 108

12.70 (s, 1H), 12.15 (s, br, 1H), 10.97 (s, 1H), 8.43 (d, J = 2.4 Hz,1H), 7.92 (dd, J¹ = 8.8 Hz, J² = 2.4 Hz, 1H), 7.86 (s, 1H), 6.87 (d, J =8.8 Hz, 1H), 4.23 (d, J = 12.8 Hz, 2H), 3.78 (t, J = 6 Hz, 2H), 3.70 (t,J = 6 Hz, 2H), 2.77 (t, J = 11.2 Hz, 2H), 2.17 (d, J = 6.8 Hz, 2H), 1.88(m, 1H), 1.73 (m, 6H), 1.49 (m, 4H), 1.29 (m, 2H) 479.2 (M + 1) 109

12.69 (s, 1H), 11.14 (s, 1H), 7.85 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H),6.94 (d, J = 8.8 Hz, 2H), 4.63 (t, J = 6 Hz, 1H), 3.79 (t, J = 6.0 Hz,2H), 3.75 (t, J = 6.0 Hz, 2H), 3.63 (d, J = 12.4 Hz, 2H), 3.39 (m, 2H),3.12 (m, 2H), 2.67 (m, 2H), 2.04 (m, 3H), 1.73 (m, 4H), 1.49 (m, 4H),1.21 (m, 5H) 521.4 (M + 1) 110

12.71 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 4.72 (t, J = 6.0 Hz, 1H), 3.95-3.73 (m, 9H),3.50-3.38 (m, 5H), 1.75 (m, 4H), 1.50 (m, 4H) 483.2 (M + 1) 111

12.69 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 3.79 (t, J = 6.0 Hz, 2H), 3.77 (m, 2H), 3.75(t, J = 6.0 Hz, 2H), 2.60 (t, J = 11.2 Hz, 2H), 1.88 (m, 7H), 1.48 (m,6H), 1.31 (s, 6H) 487.4 (M + 1) 112

12.69 (s, 1H), 11.14 (s, 1H), 7.85 (s, 1H), 7.85 (s, 1H), 7.60 (d, J =8.8 Hz, 2H), 7.01 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.79 (s, 1H), 3.79(m, 6H), 1.70-1.50 (m, 12H), 1.3 (m, 2H), 1.01 (s, 6H) 505.2 (M + 1) 113

12.69 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H),6.96 (d, J = 8.8 Hz, 2H), 3.80 (t, J = 6.0 Hz, 2H), 3.75 (t, J = 6.0 Hz,2H), 3.69 (d, J = 12.4 Hz, 2H), 2.68-2.54 (m, 6H), 1.79 (m, 5H), 1.51(m, 4H), 1.35 (m, 2H) 459.2 (M + 1) 114

12.75 (s, 1H), 10.95 (s, 1H), 8.4 (s, 1H), 7.88 (s, 1H), 7.86 (s, 1H),6.91 (d, J = 8.8 Hz, 1H), 5.75 (s, br, 2H), 4.30 (d, J = 12.4 Hz, 2H),2.96 (t, J = 11.6 Hz, 2H), 2.80 (t, J = 12 Hz, 2H), 2.50 (m, 4H),1.96-1.75 (m, 6H), 1.26 (m, 4H) 485.0 (M + 1) 115

12.71 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 5.37 (s, 1H), 4.09 (t, J = 5.6 Hz, 2H), 3.80(t, J = 5.6 Hz, 2H), 3.73 (t, J = 6.0 Hz, 2H), 2.70 (t, J = 5.2 Hz, 2H),2.50 (m, 8H), 1.75 (m, 4H), 1.50 (m, 4H), 1.30 (s, 6H) 551.1 (M + 1) 116

12.75 (s, 1H), 12.07 (s, 1H), 10.95 (s, 1H), 8.39 (d, J = 2.4 Hz, 1H),7.88 (s, 1H), 7.85 (dd, J¹ = 9.2 Hz, J² = 2.4 Hz, 1H), 6.90 (d, J = 9.2Hz, 1H), 4.56 (m, 2H), 4.24 (d, J = 12.8 Hz, 2H), 3.80 (t, J = 5.6 Hz,2H), 3.73 (t, J = 6.1 Hz, 2H), 2.18 (d, J = 7.6 Hz, 2H), 1.96-1.72 (m,8H), 1.19-1.14 (m, 4H) 504.1 (M + 1) 117

12.73 (s, 1H), 12.01 (s, br, 1H), 11.19 (s, br, 1H), 7.88 (s, 1H), 7.67(d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.67 (m, 2H), 3.65 (d, J= 12.4 Hz, 2H), 2.56 (m, 5H), 2.21 (d, J = 6 Hz, 2H), 1.79 (m, 4H), 1.57(m, 4H), 0.92 (s, 6H) 491.4 (M + 1) 118

12.69 (s, 1H), 11.14 (s, 1H), 7.85 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H),6.95 (d, J = 8.8 Hz, 2H), 4.81 (t, J = 5.6 Hz, 1H), 4.64 (t, J = 5.6 Hz,1H), 4.13 (d, J = 2 Hz, 2H), 3.81- 3.75 (m, 6H), 3.51-3.44 (m, 6H), 2.50(m, 4H), 2.30 (m, 5H), 1.75 (m, 4H), 1.50 (m, 4H) 565.1 (M + 1) 119

13.30 (s, 1H), 11.30 (s, 1H), 8.41 (d, J = 6.4 Hz, 2H), 8.28 (s, 1H),7.73 (d, J = 8.8 Hz, 2H), 7.58 (m, 3H), 7.06 (d, J = 8.8 Hz, 2H), 3.85(d, J = 12.0 Hz, 2H), 2.65 (t, J = 10.8 Hz, 2H), 1.88 (d, J = 11.6 Hz,2H), 1.49 (m, 3H), 1.36 (s, 6H) 466.2 (M + 1) 120

12.70 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 4.07 (t, J = 5.4 Hz, 2H), 3.80 (t, J = 5.6 Hz,2H), 3.73 (t, J = 6 Hz, 2H), 3.03 (d, J = 10 Hz, 2H), 2.67 (d, J = 1.6Hz, 2H), 1.98 (m, 11H), 1.50 (m, 4H), 1.27 (s, 6H) 531.0 (M + 1) 121

12.70 (s, 1H), 12.21 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.53 (d, J =8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.56 (m, 2H), 3.62 (m, 4H), 2.64(t, J = 11.4 Hz, 4H), 2.19 (d, J = 6.8 Hz, 2H), 1.75 (m, 3H), 1.33 (m,2H), 1.17 (d, J = 6.0 Hz, 6H) 494.1 (M + 1) 122

11.32 (s, 1H), 11.30 (s, 1H), 8.40 (d, J = 6.4 Hz, 2H), 8.30 (s, 1H),7.78 (d, J = 8.8 Hz, 2H), 7.57 (m, 3H), 7.08 (d, J = 8.8 Hz, 2H), 4.73(t, J = 6 Hz, 1H), 4.00 (d, J = 4.8 Hz, 2H), 3.92-3.80 (m, 3H), 3.50-3.39 (m, 5H)   462 (M + 1) 123

12.73 (s, 1H), 12.01 (s, br, 1H), 11.32 (s, 1H), 7.88 (s, 1H), 7.70 (d,J = 8.8 Hz, 2H), 7.28 (d, J = 8.8 Hz, 2H), 4.52 (s, br, 1H), 3.81-3.77(m, 4H), 2.35 (m, 3H), 1.80-1.51 (m, 16H) 477.2 (M + 1) 124

12.71 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H),6.96 (d, J = 8.8 Hz, 2H), 3.99-3.71 (m, 10H), 3.43 (m, 2H), 1.75 (m,4H), 1.50 (m, 4H) 495.4 (M − 1) 125

12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.64 (d, J = 8.8 Hz, 2H),6.96 (d, J = 8.8 Hz, 2H), 3.80 (t, J = 5.6 Hz, 2H), 3.75 (t, J = 5.6 Hz,2H), 3.65-3.16 (m, 7H), 2.71-2.66 (m, 4H), 1.75 (m, 4H), 1.51 (m, 4H)499.3 (M + 1) 126

12.71 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H),6.4 (d, J = 8.8 Hz, H), 3.98 (t, J = 6.4 Hz, 2H), 3.80 (t, J = 6.0 Hz,2H), 3.73 (t, J = 6.0 Hz, 2H), 2.84 (m, 2H), 2.45 (m, 2H), 2.12 (d, J =6.4 Hz, 2H), 1.88 (m, 7H), 1.75 (m, 4H), 1.50 (m, 4H), 1.19 (m, 2H)536.0 (M + 1) 127

12.63 (s, 1H), 12.08 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.65 (d, J =8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.42-3.10 (m, 4H), 1.99 (m, 4H),1.39-1.22 (m, 11H), 0.97- 0.92 (m, 2H) 490.2 (M + 1) 128

12.71 (s, 1H), 12.04 (s, 1H), 11.12 (s, 1H), 7.86 (s, 1H), 7.55 (d, J =8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 3.82 (m, 4H), 3.33-3.05 (m, 4H),1.78 (m, 2H), 1.65-1.53 (m, 9H), 0.98-0.92 (m, 2H) 476.2 (M + 1) 129

12.73 (s, 1H), 12.06 (s, 1H), 11.30 (s, 1H), 7.87 (s, 1H), 7.68 (d, J =8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 3.80 (t, J = 6.0 Hz, 2H), 3.76(t, J = 5.2 Hz, 2H), 2.44 (m, 1H), 2.13 (d, J = 6.8 Hz, 2H), 1.79-1.51(m, 9H), 1.47-1.23 (m, 6H), 1.15 (m, 2H) 475.4 (M − 1) 130

12.69 (s, 1H), 12.03 (s, 1H), 11.14 (s, 1H), 7.85 (s, 1H), 7.60 (d, J =8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 3.79 (t, J = 5.6 Hz, 2H), 3.74(t, J = 5.6 Hz, 2H), 3.64 (d, J = 12.8 Hz, 2H), 2.59 (t, J = 10.4 Hz,2H), 2.25 (t, J = 7.6 Hz, 2H), 1.75 (m, 6H), 1.50 (m, 6H), 1.30 (m, 1H),1.23 (m, 2H) 492.3 (M + 1) 131

12.69 (s, 1H), 12.03 (s, 1H), 11.14 (s, 1H), 7.85 (s, 1H), 7.60 (d, J =8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 3.79 (t, J = 5.6 Hz, 2H), 3.74(t, J = 5.6 Hz, 2H), 3.65 (d, J = 12.8 Hz, 2H), 2.59 (t, J = 10.4 Hz,2H), 1.76 (m, 2H), 1.74 (m, 4H), 1.50 (m, 4H), 1.45 (m, 2H), 1.23 (m,2H), 0.95-0.92 (m, 3H) 504.1 (M + 1) 132

12.59 (s, 2H), 11.28 (s, 1H), 8.40 (d, J = 6 Hz, 2H), 8.27 (s, 1H), 7.71(d, J = 8.8 Hz, 2H), 7.56 (m, 3H), 7.04 (d, J = 8.8 Hz, 2H), 3.73 (d, J= 12.4 Hz, 2H), 2.64 (t, J = 12 Hz, 2H), 2.25 (t, J = 7.2 Hz, 2H), 1.76(d, J = 11.6 Hz, 2H), 1.50 (d, J = 6.8 Hz, 2H), 1.38 (m, 1H), 1.25 (m,2H) 471.3 (M + 1) 133

13.01 (s, 2H), 11.26 (s, 1H), 8.39 (m, 2H), 8.23 (s, 1H), 7.65 (d, J =8.8 Hz, 2H), 7.34 (t, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H),3.29-3.15 (m, 4H), 1.80 (t, J = 5.8 Hz, 2H), 1.60-1.52 (m, 3H), 0.94-0.80 (m, 2H) 471.3 (M + 1) 134

12.70 (s, 1H), 12.0 (s, 1H), 10.98 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H),7.94 (dd, J¹ = 9.2 Hz, J² = 2.4 Hz, 1H), 7.86 (s, 1H), 6.90 (d, J = 9.2Hz, 1H), 3.79 (t, J = 5.2 Hz, 2H), 3.70 (t, J = 5.2 Hz, 2H), 3.61 (m,2H), 1.73 (m, 7H), 1.49 (m, 8H), 0.98-0.94 (m, 2H) 491.4 (M + 1) 135

12.75 (s, 1H), 12.06 (s, 1H), 11.30 (s, 1H), 7.90 (d, J = 2.4 Hz, 1H),7.88 (s, 1H), 7.29 (dd, J¹ = 9.6 Hz, J² = 2.4 Hz, 1H), 7.07 (t, J = 9.6Hz, 1H), 3.81 (t, J = 6.4 Hz, 2H), 3.76 (t, J = 5.6 Hz, 2H), 3.02-2.99(m, 4H), 1.79 (m, 6H), 1.54 (m, 7H), 0.98-0.92 (m, 2H) 508.4 (M + 1) 136

12.89 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H),6.95 (d, J = 8.8 Hz, 2H), 3.99 (t, J = 6.4 Hz, 2H), 3.80 (t, J = 6.4 Hz,2H), 3.73 (t, J = 6 Hz, 2H), 3.58 (s, 1H), 2.67 (m, 4H), 2.46- 2.33 (m,4H), 1.75 (m, 4H), 1.50 (m, 4H) 479.3 (M + 1) 137

13.33 (s, 1H), 12.01 (s, 1H), 11.12 (s, 1H), 8.56 (d, J = 2.4 Hz, 1H),8.37 (d, J = 8 Hz, 2H), 8.30 (s, 1H), 8.19 (dd, J¹ = 9.6 Hz, J² = 2.4Hz, 1H), 7.57 (m, 3H), 7.02 (d, J = 9.6 Hz, 1H), 3.33-3.30 (m, 4H), 1.73(m, 2H), 1.58 (m, 3H), 1.00 (m, H) 470.2 (M + 1) 138

13.05 (s, 2H), 11.35 (s, 1H), 8.80 (d, J = 3.6 Hz, 2H), 8.31 (s, 1H),8.21 (d, J = 3.6 Hz, 2H), 7.70 (d, J = 7.6 Hz, 2H), 7.06 (d, J = 7.6 Hz,2H), 3.10 (m, 4H), 1.80 (m, 2H), 1.57 (m, 3H), 0.98-0.93 (m, 2H) 470.1(M + 1) 139

12.69 (s, 2H), 11.14 (s, 1H), 7.85 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H),6.95 (d, J = 8.8 Hz, 2H), 4.11 (s, 1H), 3.79 (t, J = 6 Hz, 2H), 3.75 (t,J = 5.6 Hz, 2H), 3.72 (m, 2H), 2.50 (m, 2H), 1.78 (m, 6H), 1.50 (m, 4H),1.34 (m, 3H), 1.06 (s, 6H) 478.2 (M + 1) 140

12.70 (s, 2H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H),6.95 (d, J = 8.8 Hz, 2H), 3.80 (t, J = 6 Hz, 2H), 3.75 (t, J = 6 Hz,2H), 3.16 (m, 4H), 2.76 (m, 4H), 1.75 (m, 4H), 1.50 (m, 4H), 1.25 (s,6H) 507.2 (M + 1) 141

12.75 (s, 1H), 12.0 (s, 1H), 11.14 (s, 1H), 7.84 (s, 1H), 7.60 (d, J =8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 3.75 (t, J = 6 Hz, 2H), 3.70 (t,J = 5.6 Hz, 2H), 3.21 (m, 3H), 1.79 (m, 8H), 1.51-1.41 (m, 8H), 0.84 (m,4H), 0.66 (m, 1H) 504.2 (M + 1) 142

12.69 (s, 1H), 12.02 (s, 1H), 11.14 (s, 1H), 7.85 (s, 1H), 7.60 (d, J =8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 3.79 (t, J = 5.6 Hz, 2H), 3.74(t, J = 5.2 Hz, 2H), 3.70 (m, 2H), 2.5 (m, 2H), 1.76 (m, 4H), 1.60- 1.50(m, 7H), 1.37 (m, 2H), 1.05 (s, 6H) 506.2 (M + 1) 143

13.30 (s, 1H), 12.4 (s, 1H), 11.30 (s, 1H), 8.41 (d, J = 6 Hz, 2H), 8.29(s, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.58 (m, 3H), 7.05 (d, J = 8.8 Hz,2H), 3.80 (d, J = 12 Hz, 2H), 2.61 (t, J = 11.2 Hz, 2H), 1.65- 1.62 (m,3H), 1.43-1.37 (m, 2H), 1.07 (s, 6H) 485.0 (M + 1) 144

12.71 (bs, 1H), 11.00 (bs, 1H), 8.46 (bs, 1H), 7.96-7.86 (m, 2H), 6.88(bs, 1H), 3.78-3.70 (m, 4H), 3.49 (m, 4H), 3.19 (m, 4H), 2.66 (bs, 2H),1.73-1.50 (m, 8H) 480.0 145

12.67 (s, 1H), 11.09 (s, 1H), 7.84 (s, 1H), 7.57 (d, J = 9.3 Hz, 2H),6.73 (d, J = 8.8 Hz, 2H), 3.81-3.73 (m, 6H), 3.57-3.43 (m, 4H), 2.98 (t,J = 4.4 Hz, 2H), 2.82 (t, J = 5.2 Hz, 2H), 1.96-1.94 (m, 2H), 1.78- 1.74(m, 4H), 1.51 (m, 4H) 493.3 146

12.75 (s, 1H), 11.13 (s, 1H), 7.84 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 4.12 (s, 1H), 4.65 (m, 2H), 3.76-3.74 (m, 2H),3.01-2.95 (m, 2H), 2.55-2.53 (m, 4H), 1.97 (m, 1H), 1.84-1.77 (m, 4H),1.35-1.21 (m, 4H), 1.06 (s, 6H) 503.4 147

12.75 (s, 1H), 12.01 (s, 1H), 11.12 (s, 1H), 7.87 (s, 1H), 7.54 (d, J =7.3 Hz, 2H), 6.97 (d, J = 7.4 Hz, 2H), 4.77 (m, 2H), 3.66 (m, 2H), 2.98(m, 2H), 2.60 (m, 4H), 2.26 (m, 2H), 1.97 (m, 1H), 1.83-1.82 (m, 2H),1.75-1.72 (m, 2H), 1.50- 1.37 (m, 3H), 1.23 (m, 4H) 517.3 148

12.76 (s, 1H), 12.05 (s, 1H), 10.96 (s, 1H), 8.40 (s, 1H), 7.88 (s, 2H),6.93 (s, 1H), 4.61-4.51 (m, 3H), 3.55-3.52 (m, 4H), 2.66-2.96 (m, 3H),1.56-1.46 (m, 10H), 1.48-1.23 (m, 4H), 0.85-0.97 (m, 3H) 516.3 149

12.80 (bs, 1H), 11.15 (s, 1H), 7.90 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H),6.98 (d, J = 8.8 Hz, 2H), 4.13 (m, 2H), 4.08 (t, J = 5.7 Hz, 4H), 3.64-3.59 (m, 2H), 3.39-3.37 (m, 2H), 3.18 (t, J = 4.2 Hz, 2H), 2.79 (m, 4H),2.68 (t, J = 5.9 Hz, 2H), 1.95 (q, J = 3.4 Hz, 2H), 1.76-1.73 (m, 2H)476.1 150

12.80 (bs, 1H), 11.15 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 9.3 Hz, 2H),6.99 (d, J = 9.3 Hz, 2H), 4.80-4.60 (m, 3H), 4.07 (t, J = 5.9 Hz, 2H),3.01-2.95 (m, 3H), 2.72-2.53 (m, 6H), 2.41-2.32 (m, 4H), 1.98-1.81 (m,4H), 1.24-1.21 (m, 2H) 490.3 151

12.72 (s, 1H), 11.18 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 9.3 Hz, 2H),6.97 (d, J = 9.3 Hz, 2H), 4.07 (t, J = 5.7 Hz, 2H), 3.80 (t, J = 6.1 Hz,2H), 3.74 (t, J = 5.9 Hz, 2H) 493.4 152

11.31 (s, 1H), 8.40 (d, J = 6.3 Hz, 2H), 8.30 (s, 1H), 7.78 (d, J = 8.8Hz, 2H), 7.61-7.54 (m, 3H), 7.06 (d, J = 8.8 Hz, 2H), 4.11 (t, J = 5.9Hz, 2H), 2.70-2.66 (m, 6H), 2.42 (m, 4H) 444.2 153

12.65 (bs, 1H), 11.1 (s, 1H), 7.87 (s, 1H), 7.60 (d, J = 9.3 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 4.07 (t, J = 5.7 Hz, 2H), 3.81 (m, 4H), 2.68(m, 4H), 2.64 (t, J = 5.9 Hz, 2H), 2.39 (m, 4H), 1.65-1.64 (m, 2H), 1.55(m, 4H) 451.3 154

12.69 (s, 1H), 11.06 (s, 1H), 7.84 (s, 1H), 7.51 (d, J = 9.2 Hz, 2H),6.73 (d, J = 8.8 Hz, 2H), 3.81 (m, 4H), 3.64-3.54 (m, 4H), 3.45 (t, J =6.1 Hz, 2H), 2.97 (t, J = 4.4 Hz, 2H), 2.81 (t, J = 5.2 Hz, 2H), 1.93(t, J = 5.1 Hz, 2H), 1.65-1.64 (m, 2H), 1.54 (m, 4H) 479.2 155

12.79 (s, 1H), 11.30 (s, 1H), 7.90 (s, 1H), 7.72 (m, 2H), 7.38 (m, 2H),4.74-4.65 (m, 2H), 3.17-2.98 (m, 4H), 1.99-1.91 (m, 3H), 1.74- 1.62 (m,8H), 1.23-1.01 (m, 4H), 0.93 (d, J = 5.9 Hz, 3H) 490.3 156

12.82 (s, 1H), 11.22 (s, 1H), 9.65 (s, 2H), 7.93 (s, 1H), 7.67 (d, J =9.3 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 4.75-4.63 (m, 2H), 4.43 (d, J =4.4 Hz, 2H), 3.83-3.50 (m, 8H), 2.97 (m, 2H), 1.73-1.70 (m, 4H),1.11-1.07 (m, 3H), 0.93 (d, J = 6.4 Hz, 3H) 465.3 157

12.72 (s, 1H), 11.18 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 7.8 Hz, 2H),6.98 (d, J = 7.8 Hz, 2H), 4.12 (s, 2H), 3.80-3.74 (m, 4H), 3.17- 3.07(m, 4H), 2.78-2.69 (m, 4H), 1.76 (m, 4H), 1.51 (m, 4H) 479.0 158

12.71 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 9.3 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 4.07 (t, J = 5.9 Hz, 2H), 3.80 (t, J = 6.1 Hz,2H), 3.73 (t, J = 5.9 Hz, 2H), 2.69 (t, J = 5.9 Hz, 2H), 2.33-2.31 (m,2H), 1.75-1.65 (m, 7H), 1.50-1.41 (m, 8H), 0.88-0.78 (m, 2H) 534.0 159

12.72 (s, 1H), 11.19 (s, 1H), 7.87 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H),6.98 (d, J = 8.8 Hz, 2H), 4.07 (m, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.74(t, J = 5.8 Hz, 2H), 3.0-2.80 (m, 2H), 2.68-2.53 (m, 4H), 1.76 (m, 4H),1.51 (m, 4H), 1.03 (m, 6H) 452.4 160

12.67 (s, 1H), 11.18-11.11 (m, 1H), 7.87 (s, 1H), 7.65 (d, J = 8.8 Hz,2H), 6.96 (d, J = 8.8 Hz, 2H), 4.08 (t, J = 5.9 Hz, 2H), 3.07-3.02 (m,3H), 2.69-2.63 (m, 6H), 2.39 (m, 4H), 1.86-1.70 (m, 2H), 1.67- 1.53 (m,6H), 1.40-1.14 (m, 4H) 479.0 161

12.71 (s, 1H), 12.10 (bs, 1H), 11.15-11.08 (m, 1H), 7.86 (s, 1H), 7.59(d, J = 8.3 Hz, 2H), 6.95 (d, J = 8.4 Hz, 2H), 3.65-3.60 (m, 2H),3.06-3.03 (m, 3H), 2.67-2.61 (m, 2H), 2.19 (d, J = 6.3 Hz, 2H), 1.82-1.52 (m, 10H), 1.50-1.14 (m, 6H) 492.1 162

12.76 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.57 (d, J = 8.9 Hz, 2H),6.99 (d, J = 8.8 Hz, 2H), 4.95-4.60 (m, 2H), 3.20-3.15 (m, 6H), 3.02-2.99 (m, 2H), 2.72-2.67 (m, 4H), 2.55-2.53 (m, 4H), 2.1-1.95 (m, 1H),1.84-1.81 (m, 2H), 1.24-1.21 (m, 2H) 504.2 163

13.31 (s, 1H), 11.26 (s, 1H), 8.29 (s, 1H), 8.00 (d, J = 7.8 Hz, 2H),7.95 (d, J = 2.5 Hz, 1H), 7.72 (d, J = 8.8 Hz, 2H), 7.48 (t, J = 7.6 Hz,1H), 7.17 (dd, J₁ = 2.4 Hz, J₂ = 7.8 Hz, 1H), 7.05 (d, J = 9.3 Hz, 2H),3.86 (s, 3H), 3.76 (m, 2H), 2.74- 2.56 (m, 4H), 1.83-1.80 (m, 3H),1.42-1.38 (m, 2H)   466 (M − 1) 164

11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 9.2 Hz, 2H), 6.96 (d, J = 8.8Hz, 2H), 4.04 (t, J = 6.1 Hz, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.74 (t, J= 5.9 Hz, 2H), 2.86 (t, J = 6.2 Hz, 2H), 2.79-2.67 (m, 7H), 1.75 (m,4H), 1.69-1.63 (m, 2H), 1.50 (m, 4H) 491.4 165

12.70 (s, 1H), 11.17 (s, 1H), 8.03 (s, 1H), 7.86 (s, 1H), 7.65 (d, J =9.3 Hz, 2H), 6.97 (d, J = 9.2 Hz, 2H), 3.80 (t, J = 5.9 Hz, 2H), 3.75(t, J = 5.9 Hz, 2H), 3.70 (s, 2H), 3.40-3.38 (m, 2H), 3.30-3.29 (m, 2H),1.79-1.75 (m, 4H), 1.15 (m, 4H) 435.3 166

11.27 (s, 1H), 8.03 (s, 1H), 8.01 (d, J = 7.3 Hz, 1H), 7.94 (s, 1H),7.78 (d, J = 8.8 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.16 (d, J = 7.3 Hz,2H), 7.06 (d, J = 8.30 Hz, 2H), 4.11 (m, 2H), 3.86 (s, 3H), 2.71-2.67(m, 6H), 2.42 (m, 4H) 474.2 167

12.71 (s, 1H), 11.18 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 4.05 (t, J = 5.6 Hz, 2H), 3.80 (t, J = 6.2 Hz,2H), 3.74 (t, J = 5.9 Hz, 2H), 2.65 (t, 5.6 Hz, 2H), 2.24 (s, 6H), 1.76(m, 4H), 1.51 (m, 4H) 424.1 168

11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8Hz, 2H), 4.00 (t, J = 6.6 Hz, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.74 (t, J= 5.9 Hz, 2H), 2.91-2.89 (m, 2H), 2.43 (m, 2H), 1.76 (m, 4H), 1.65- 1.60(m, 4H), 1.51 (m, 4H), 1.09- 1.01 (m, 2H) 464.1 169

11.15 (s, 1H), 7.94 (s, 1H), 7.75 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 8.8Hz, 2H), 4.79-4.68 (m, 4H), 4.00 (t, J = 6.4 Hz, 2H), 3.02-2.90 (m, 4H),2.45-2.42 (m, 2H), 1.97 (m, 1H), 1.84-1.81 (m, 2H), 1.64-1.54 (m, 4H),1.34-1.23 (m, 2H), 1.12- 1.06 (m, 2H) 489.1 170

12.70 (bs, 1H), 11.15-11.09 (m, 1H), 7.86 (s, 1H), 7.60 (d, J = 8.3 Hz,2H), 6.97 (d, J = 8.8 Hz, 2H), 4.80-4.49 (m, 2H), 3.22-3.03 (m, 4H),1.83-1.52 (m, 13H), 1.40-1.34 (m, 2H), 1.31-1.14 (m, 2H), 0.96- 0.91 (m,2H) 502.3 171

11.14 (s, 1H), 7.86 (s, 1H), 7.60 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 8.8Hz, 2H), 4.04 (t, J = 6.1 Hz, 2H), 3.81 (m, 4H), 2.86 (t, J = 6.2 Hz,2H), 2.79-2.67 (m, 6H), 1.67-1.63 (m, 4H), 1.54 (m, 4H) 477.2 172

12.71 (bs, 1H), 11.18 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H),6.97 (d, J= 8.8 Hz, 2H), 4.56 (bs, 1H), 4.07 (m, 2H), 3.80 (t, J = 5.7Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.46 (m, 1H) 2.8-2.67 (m, 4H),1.75-1.74 (m, 6H), 2.33-2.16 (m, 2H), 1.51-1.40 (m, 4H), 1.30-1.17 (m,2H) 480.1 173

12.65 (bs, 1H), 11.29 (s, 1H), 7.88 (s, 1H), 7.67 (d, J = 8.3 Hz, 2H),7.21 (d, J = 8.3 Hz, 2H), 3.80 (t, J = 5.7 Hz, 2H), 3.74 (t, J = 5.9 Hz,2H), 2.68 (m, 4H) 2.56-2.54 (m, 2H), 2.25-2.20 (m, 6H), 1.74-1.67 (m,6H), 1.51 (m, 4H) 463.4 174

12.70 (bs, 1H), 11.27 (s, 1H), 7.90 (s, 1H), 7.61 (d, J = 8.3 Hz, 2H),7.24 (d, J = 8.3 Hz, 2H), 4.78-4.71 (m, 2H), 3.00 (m, 2H), 2.68 (m, 4H),2.59-2.54 (m, 4H), 2.25-2.21 (m, 6H), 1.98 (m, 2H), 1.85-1.82 (m, 2H),1.75-1.68 (m, 2H), 1.23- 1.22 (m, 2H) 488.2 175

12.70 (bs, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H),6.98 (d, J = 8.3 Hz, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.77-3.74 (m, 4H),3.46-3.41 (m, 4H), 3.39-3.35 (m, 2H), 1.79-1.75 (m, 4H), 1.51 (m, 4H),1.07 (t, J = 7.1 Hz, 3H) 463.2 176

12.82 (s, 1H), 11.18 (s, 1H), 7.90 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H),6.98 (d, J = 8.8 Hz, 2H), 4.07 (t, J = 5.9 Hz, 2H), 3.80 (m, 4H),3.68-3.67 (m, 4H), 2.72 (t, J = 4.7 Hz, 4H), 2.68-2.66 (m, 2H), 2.42-2.32 (m, 4H) 453.2 177

12.82 (s, 1H), 11.50 (bs, 1H), 7.92 (s, 1H), 7.60 (d, J = 8.8 Hz, H),6.99 (d, J = 9.3 Hz, 2H), 4.55 (m, 2H), 4.07 (t, J = 5.9 Hz, 2H), 3.57-3.55 (m, 2H), 3.27-3.20 (m, 2H), 2.69-2.66 (m, 4H), 2.39-2.30 (m, 6H),1.16 (d, J = 5.8 Hz, 6H) 481.0 178

12.76 (s, 1H), 11.15 (s, 1H), 7.88 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H),7.00 (d, J = 9.3 Hz, 2H), 4.78-4.71 (m, 2H), 3.75 (s, 2H), 3.48-3.43 (m,4H), 3.38 (q, J = 7.1 Hz, 2H), 3.02-2.96 (m, 2H), 2.55-2.54 (m, 2H),2.55-2.54 (m, 2H), 1.98-1.97 (m, 1H), 1.84-1.81 (m, 2H), 1.23- 1.21 (m,4H), 1.07 (t, J = 7.1 Hz, 3H); MS m/z 488.3 179

12.73 (s, 1H), 11.29 (s, 1H), 7.88 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H),7.21 (d, J = 8.4 Hz, 2H), 4.51 (d, J = 3.9 Hz, 1H), 3.81 (t, J = 6.1 Hz,2H), 3.75 (t, J = 5.9 Hz, 2H), 3.4 (m, 1H), 2.67 (m, 2H), 2.56 (t, J =7.6 Hz, 2H), 2.23 (t, J = 6.9 Hz, 2H), 1.97-1.92 (m, 2H), 1.76-1.68 (m,8H), 1.51 (m, 4H), 1.38-1.21 (m, 2H) 478.3 180

12.7 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H),6.96 (d, J = 9.3 Hz, 2H), 3.51 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 5.9 Hz,2H), 3.27-3.14 (m, 4H), 2.45 (m, 6H), 1.77-1.75 (m, 4H), 1.51 (m, 4H),1.05 (t, J = 7.1 Hz, 3H) 449.1 181

12.70 (bs, 1H), 11.03 (s, 1H), 8.47 (d, J = 1.4 Hz, 1H), 7.98 (dd, J₁ =2.2 Hz, J₂ = 8.6 Hz, 1H), 7.88 (s, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.34(t, J = 5.9 Hz, 2H), 3.79 (m, 4H), 2.67-2.62 (m, 7H), 2.38-2.33 (m, 4H),1.63 (m, 2H), 1.54 (m, 4H) 452.1 182

12.70 (bs, 1H), 11.06 (s, 1H), 8.49 (d, J = 2.5 Hz, 1H), 8.05 (dd, J₁ =2.8 Hz, J₂ = 9.1 Hz, 1H), 7.88 (s, 1H), 6.85 (d, J = 9.3 Hz, 1H), 4.34(t, J = 6.2 Hz, 2H), 3.79 (t, J = 6.1 Hz, 2H), 3.69 (t, J = 5.9 Hz, 2H),2.68-2.67 (m, 4H), 2.63 (t, J = 5.9 Hz, 2H), 2.38 (m, 4H), 1.72 (m, 4H),1.50 (m, 4H) 466.4 183

12.73 (s, 1H), 11.14 (s, 1H), 7.87 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H),6.98 (d, J = 8.8 Hz, 2H), 4.57 (bs, 1H), 4.08 (m, 2H), 3.81 (m, 4H),3.46 (m, 1H), 2.82-2.53 (m, 4H), 2.33-2.18 (m, 2H), 1.73-1.37 (m, 10H)466.4 184

12.72 (s, 1H), 11.19 (s, 1H), 7.87 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H),6.99 (d, J = 8.8 Hz, 2H), 4.14-4.07 (m, 3H), 3.80 (t, J = 6.1 Hz, 2H),3.74 (t, J = 5.9 Hz, 2H), 3.18-3.16 (m, 6H), 1.91 (m, 4H), 1.76 (m, 8H),1.13 (s, 3H) 494.4 185

12.77 (s, 1H), 11.16 (s, 1H), 7.87 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H),6.99 (d, J = 8.8 Hz, 2H), 4.80-4.68 (m, 3H), 4.10 (m, 3H), 3.02-2.95 (m,2H), 2.70-2.53 (m, 6H), 1.98- 1.95 (m, 1H), 1.84-1.81 (m, 2H), 1.49 (m,4H), 1.26-1.21 (m, 4H), 1.11 (s, 3H) 519.3 186

12.69 (s, 1H), 11.14 (s, 1H), 7.86 (s, 1H), 7.60 (d, J = 9.3 Hz, 2H),6.95 (d, J = 8.8 Hz, 2H), 4.66 (d, J = 3.9 Hz, 1H), 3.80 (t, J = 6.2 Hz,2H), 3.75 (d, J = 5.9 Hz, 2H), 3.62- 3.60 (m, 1H), 3.52-3.49 (m, 2H),2.84-2.79 (m, 2H), 1.82-1.76 (m, 6H), 1.48-1.46 (m, 6H) 436.2 187

12.75 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.57 (d, J = 7.4 Hz, 2H),6.98 (d, J = 9.3 Hz, 2H), 4.80-4.60 (m, 2H), 3.15 (m, 4H), 3.02-2.96 (m,2H), 2.57-2.53 (m, 6H), 2.45- 2.44 (m, 2H), 1.91 (m, 1H), 1.83 (m, 2H),1.24 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H) 474.3 188

12.72 (s, 1H), 11.18 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 9.3 Hz, 2H),6.95 (d, J = 8.8 Hz, 2H), 3.92 (m, 2H), 3.80 (d, J = 6.1 Hz, 2H), 3.74(d, J = 6.0 Hz, 2H), 3.05 (m, 2H), 2.87-2.76 (m, 2H), 1.76 (m, 4H), 1.51(, 4H), 1.02 (m, 12H) 480.3 189

12.75 (s, 1H), 11.12 (s, 1H), 7.87 (s, 1H), 7.53 (d, J = 9.3 Hz, 2H),6.97 (d, J = 9.3 Hz, 2H), 4.76-4.71 (m, 2H), 6.66 (d, J = 4.4 Hz, 1H),3.64-3.59 (m, 1H), 3.53-3.50 (m, 2H), 3.02-2.95 (m, 2H), 2.86-2.80 (m,2H), 1.97-1.91 (m, 1H), 1.84- 1.80 (m, 4H), 1.49-1.46 (m, 2H), 1.27-1.21(m, 4H) 461.1 190

12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H),6.95 (d, J = 9.3 Hz, 2H), 4.44 (m, 1H), 3.80 (t, J = 6.2 Hz, 2H), 3.65(t, J = 5.9 Hz, 2H), 3.54 (m, 2H), 3.12 (t, J = 4.9 Hz, 4H), 2.57 (t, J= 4.9 Hz, 4H), 2.45 (t, J = 6.1 Hz, 2H), 1.91-1.75 (m, 4H), 1.51 (m,4H); MS m/z 465.3 191

12.75 (s, 1H), 11.14 (s, 1H), 7.87 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H),6.97 (d, J = 9.3 Hz, 2H), 4.77 (m, 2H), 4.44 (m, 1H), 3.56-3.52 (m, 2H),3.13-3.11 (m, 4H), 3.02-2.95 (m, 2H), 2.56-2.52 (m, 4H), 2.46- 2.45 (m,2H), 2.01-1.95 (m, 1H), 1.84-1.81 (m, 2H), 1.23-1.21 (m, 4H); MS m/z490.1 192

12.70 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H),6.94 (d, J = 9.3 Hz, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 5.9 Hz,2H), 3.05-3.03 (m, 4H), 2.85 (t, J = 4.4 Hz, 4H), 1.76 (m, 4H), 1.51 (m,4H); MS m/z 421.1 193

12.73 (s, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H),6.96 (d, J = 8.8 Hz, 2H), 4.77-4.71 (m, 2H), 3.04 (m, 4H), 2.83 (m, 4H),2.55-2.53 (m, 4H), 1.97-1.94 (m, 1H), 1.84-1.81 (m, 2H), 1.23- 1.21 (m,2H) 446.1 194

12.69 (s, 1H), 11.14 (s, 1H), 7.86 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H),6.94 (d, J = 9.3 Hz, 2H), 4.36 (t, J = 5.1 Hz, 1H), 3.80 (t, J = 6.1 Hz,2H), 3.75 (t, J = 5.9 Hz, 2H), 3.66- 3.63 (m, 2H), 3.39 (q, J = 5.1 Hz,2H), 2.63-2.57 (m, 2H), 1.75-1.73 (m, 6H), 1.51-1.42 (m, 6H), 1.35- 1.30(m, 1H), 1.28-1.19 (m, 4H) 478.2 195

12.69 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H),6.95 (d, J = 9.3 Hz, 2H), 4.36 (t, J = 5.2 Hz, 1H), 3.80 (t, J = 6.2 Hz,2H), 3.75 (t, J = 5.9 Hz, 2H), 3.66- 3.63 (m, 2H), 3.47 (q, J = 5.9 Hz,2H), 2.63-2.57 (m, 2H), 1.75-1.73 (m, 6H), 1.51 (m, 5H), 1.40 (q, J =6.9 Hz, 2H), 1.26-1.22 (m, 2H) 464.2 196

12.75 (s, 1H), 11.12 (s, 1H), 7.87 (s, 1H), 7.54 (d, J = 9.3 Hz, 2H),6.97 (d, J = 9.3 Hz, 2H), 4.76 (m, 2H), 4.36 (t, J = 5.2 Hz, 1H), 3.01-2.95 (m, 2H), 3.47 (q, J = 6.4 Hz, 2H), 3.01-2.95 (m, 2H), 2.64-2.58 (m,2H), 2.55-2.52 (m, 2H), 1.98- 1.94 (m, 1H), 1.84-1.81 (m, 2H), 1.76-1.72(m, 2H), 1.56-1.51 (m, 1H), 1.40 (q, J = 6.4 Hz, 2H), 1.29- 1.20 (m, 2H)489.1 197

12.79 (s, 1H), 11.28 (s, 1H), 7.90 (s, 1H), 7.62 (d, J = 8.3 Hz, 2H),7.26 (d, J = 8.3 Hz, 2H), 4.79-4.71 (m, 2H), 3.01 (m, 2H), 2.75-2.71 (m,2H), 2.55-2.54 (m, 6H), 2.33- 2.28 (m, 6H), 1.98-1.97 (m, 1H), 1.85-1.82(m, 2H), 1.23-1.22 (m, 2H), 1.02 (t, J = 6.9 Hz, 3H) 502.3 198

12.70 (bs, 1H), 11.30 (s, 1H), 7.88 (s, 1H), 7.67 (d, J = 8.3 Hz, 2H),7.23 (d, J = 8.3 Hz, 2H), 3.81 (t, J = 6.1 Hz, 2H), 3.76 (t, J = 5.9 Hz,2H), 2.72-2.68 (m, 6H), 2.48-2.44 (m, 2H), 2.36 (m, 4H), 1.78-1.75 (m,4H), 1.51 (m, 4H) 449.2 199

11.17 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 9.3Hz, 2H), 3.96 (t, J = 5.6 Hz, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.74 (t, J= 6.1 Hz, 2H), 2.90 (t, J = 5.6 Hz, 2H), 1.75 (m, 4H), 1.51 (m, 4H)396.2 200

11.15 (s, 1H), 7.89 (s, 1H), 7.62 (d, J = 9.3 Hz, 2H), 7.00 (d, J = 8.8Hz, 2H), 4.78-4.68 (m, 2H), 3.98 (t, J = 5.4 Hz, 2H), 3.02-2.94 (m, 4H),2.55-2.53 (m, 4H), 1.97-1.94 (m, 1H), 1.84-1.81 (m, 2H), 1.23- 1.18 (m,2H) 421.2 201

12.75 (s, 1H), 11.35 (s, 1H), 7.89 (s, 1H), 7.74 (d, J = 8.3 Hz, 2H),7.28 (d, J = 8.3 Hz, 2H), 4.90 (m, 1H), 3.81 (t, J = 5.9 Hz, 2H), 3.77(t, J = 5.6 Hz, 2H), 3.6 (m, 2H), 3.16-3.13 (m, 2H), 2.92 (m, 4H),1.85-1.77 (m, 5H), 1.52 (m, 6H) 464.2 202

12.70 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 9.2 Hz, 2H),6.95 (d, J = 9.3 Hz, 2H), 4.47 (t, J = 5.4 Hz, 1H), 4.34 (m, 2H), 3.80(t, J = 6.2 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.69-3.66 (m, 2H), 3.29(t, J = 5.9 Hz, 2H), 2.64-2.58 (m, 2H), 2.4-2.26 (m, 3H), 1.76-1.73 (m,4H), 1.51 (m, 4H) 450.2 203

12.71 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H),6.97 (d, J = 9.3 Hz, 2H), 4.40 (t, J = 5.4 Hz, 1H), 4.07 (t, J = 5.7 Hz,2H), 3.80 (t, J = 6.1 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.24 (t, J =5.6 Hz, 2H), 2.96-2.94 (m, 2H), 2.68- 2.67 (m, 2H), 2.02 (m, 2H)H, 1.76(m, 2044H), 1.65-1.62 (m, 2H), 1.51 (m, 4H), 1.43 (m, 1H), 1.15- 1.07(m, 2H) 494.4 204

12.52 (s, 1H), 8.90 (d, J = 6.9 Hz, 1H), 7.79 (s, 1H), 4.48-4.46 (m,2H), 3.91-3.87 (m, 2H), 3.76 (t, J = 5.9 Hz, 2H), 3.71 (t, J = 5.8 Hz,2H), 2.93-2.91 (m, 2H), 2.78 (m, 2H), 2.47-2.45 (m, 4H), 2.37-2.20 (m,1H), 1.97-1.91 (m, 5H), 1.71- 1.48 (m, 12H) 494.4 205

12.75 (s, 1H), 11.12 (s, 1H), 7.87 (s, 1H) 7.54 (d, J = 8.8 Hz, 1H),6.97 (d, J = 9.3 Hz, 2H), 4.76 (m, 2H), 4.36 (t, J = 5.1 Hz, 1H), 3.68-3.65 (m, 2H), 3.39 (q, J = 6.3 Hz, 2H) (, 3.01-2.95 (m, 2H), 2.64-2.58(m, 2H), 2.55-2.52 (m, 2H), 1.97- 1.94 (m, 1H), 1.84-1.81 (m, 2H),1.75-1.73 (m, 2H), 1.50-1.44 (m, 2H), 1.43-1.31 (m, 1H), 1.28-1.20 (m,6H) 503.5 206

12.70 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.64 (d, J = 9.3 Hz, 2H),6.98 (d, J = 8.8 Hz, 2H), 3.82-3.78 (m, 4H), 3.75 (t, J = 5.9 Hz, 2H),3.17 (t, J = 4.7 Hz, 4H) 2.63 (t, J = 4.7 Hz, 4H), 1.78-1.75 (m, 4H),1.51 (m, 4H) 460.3 207

12.76 (s, 1H), 11.15 (s, 1H), 7.88 (s, 1H) 7.58 (d, J = 8.8 Hz, 2H),7.00 (d, J = 8.8 Hz, 2H), 4.78-4.72 (m, 2H), 3.80 (s, 2H), 3.18 (t, J =4.9 Hz, 4H), 2.63 (t, J = 4.9 Hz, 4H), 2.55-2.53 (m, 2H), 1.98-1.95 (m,1H), 1.84-1.81 (m, 2H), 1.26- 1.18 (m, 2H) 485.3 208

12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 9.3 Hz, 2H),6.96 (d, J = 8.8 Hz, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz,2H), 3.11-3.10 (m, 4H), 2.61-2.60 (m, 2H), 2.55-2.54 (m, 4H), 2.44- 2.40(m, 2H), 1.77-1.75 (m, 4H), 1.51 (m, 4H) 493.4 209

12.70 (s, 1H), 11.90 (s, 1H), 7.86 (s, 1H), 7.91 (s, 1H), 7.68 (d, J =8.3 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 3.78 (m, 4H), 2.72-2.55 (m, 4H),2.33-2.26 (m, 10H), 1.76 (m, 4H), 1.51 (m, 4H), 0.98 (t, J = 7.1 Hz, 3H)477.3 210

12.73 (s, 1H), 11.30 (s, 1H), 7.88 (s, 1H), 7.67 (d, J = 8.3 Hz, 2H),7.23 (d, J = 8.3 Hz, 2H), 4.08 (s, 1H), 3.81 (t, J = 5.9 Hz, 2H), 3.76(t, J = 5.9 Hz, 2H), 2.72-2.68 (m, 2H), 2.43-2.33 (m, 4H), 1.79-1.75 (m,4H), 1.51 (m, 4H), 1.47-1.44 (m, 4H), 1.09 (s, 3H) 478.0 211

12.74 (s, 1H), 11.30 (s, 1H), 7.88 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H),7.23 (d, J = 8.7 Hz, 2H), 4.51-4.44 (m, 1H), 3.81 (t, J = 6.2 Hz, 2H),3.76 (t, J = 5.9 Hz, 2H), 3.49 (q, J = 6.2 Hz, 2H), 2.73-2.68 (m, 2H),2.45-2.32 (m, 6H), 2.28-2.24 (m, 6H), 1.79-1.75 (m, 4H) 493.4 212

12.79 (s, 1H), 11.28 (s, 1H), 7.90 (s, 1H), 7.62 (d, J = 7.8 Hz, 2H),7.26 (d, J = 7.9 Hz, 2H), 4.80-4.70 (m, 2H), 4.41 (m, 1H), 3.49 (m, 2H),3.27-3.01 (m, 2H), 2.72-2.67 (m, 2H), 2.60 (m, 8H), 2.45-2.33 (m, 8H),1.98 (m, 1H), 1.85-1.82 (m, 2H) 518.3 213

12.77 (s, 1H), 11.19 (s, 1H), 7.89 (s, 1H), 7.63 (d, J = 6.8 Hz, 2H),7.06 (m, 2H), 4.72 (m, 2H), 3.59 (m, 8H), 3.00 (m, 2H), 1.98 (m, 1H),1.84-1.82 (m, 2H), 1.55 (s, 6H), 1.24 (m, 4H) 532.4 214

12.70 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.64 (d, J = 8.8 Hz, 2H),7.00 (d, J = 9.3 Hz, 2H), 5.46 s, 1H), 3.80 (t, J = 6.0 Hz, 2H), 3.75(t, J = 5.9 Hz, 2H), 3.29 (m, 4H), 3.12 (m, 4H), 1.77-1.75 n(m, 4H),1.51 (m, 4H), 1.34 (s, 6H) 507.3 215

12.71 (s, 1H), 11.18 (s, 1H), 7.87 (s, 1H), 7.65 (d, J = 9.3 Hz, 2H),7.00 (d, J = 9.3 Hz, 2H), 4.10 (s, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.75(t, J = 5.9 Hz, 2H), 3.61 (t, J = 5.2 Hz, 2H), 3.17 (t, J = 5.2 Hz, 2H),3.11 (t, J = 5.2 Hz, 2H), 1.77-1.75 (m, 4H), 1.51 (m, 4H) 488.4 216

12.75 (s, 1H), 11.12 (s, 1H), 7.87 (s, 1H), 7.54 (d, J = 9.3 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 4.71 (m, 2H), 4.47 (t, J = 5.4 Hz, 1H), 3.70-3.67 (m, 2H), 3.29 (t, J = 5.9 Hz, 2H), 3.01-2.95 (m, 2H), 2.62-2.52 (m,4H), 1.97 (m, 1H), 1.84-1.81 (m, 2H), 1.76-1.73 (m, 2H), 1.51- 1.28 (m,1H), 1.25-1.21 (m, 4H) 475.2 217

12.70 (s, 1H), 10.97 (s, 1H), 8.43 (d, J = 2.5 Hz, 1H), 7.93 (d, J = 8.8Hz, 2H), 7.86 (s, 1H), 6.88 (d, J = 9.3 Hz, 1H), 4.68 (d, J = 4.4 Hz,1H), 4.00-3.94 (m, 2H), 3.79 (t, J = 5.9 Hz, 2H), 3.70 (t, J = 5.9 Hz,2H), 3.67-3.66 (m, 1H), 3.08-3.02 (m, 2H), 1.79-1.73 (m, 6H), 1.50 (m,4H), 1.41-1.32 (m, 2H) 437.3 218

12.77 (s, 1H), 11.15 (s, 1H), 7.88 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H),6.98 (d, J = 9.3 Hz, 2H), 4.86-4.68 (m, 2H), 4.40 (t, J = 5.1 Hz, 1H),4.07 (d, J = 5.7 Hz, 2H), 3.24 (t, J = 5.9 Hz, 2H), 3.1-2.92 (m, 4H),2.67 (m, 4H), 2.55-2.53 (m, 1H), 1.99-1.96 (m, 5H), 1.84-1.81 (m, 4H),1.64-1.61 (m, 4H), 1.34-1.33 (m, 1H), 1.26-1.11 (m, 4H) 519.3 219

12.70 (s, 1H), 11.17 (s, 1H), 7.88 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H),7.01 (d, J = 8.4 Hz, 2H), 5.53-5.43 (m, 2H), 3.80 (t, J= 6.2 Hz, 2H),3.75 (t, J = 5.9 Hz, 2H), 3.27-3.06 (m, 3H), 1.77-1.70 (m, 6H), 1.59-1.51 (m, 6H), 1.13-1.09 (m, 2H) 598.4 220

12.75 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H),6.98 (d, J = 8.8 Hz, 2H), 4.80-4.60 (m, 2H), 3.13-3.11 (m, 4H), 3.02-2.95 (m, 2H), 2.61-2.52 (m, 6H), 2.42 (t, J = 7.1 Hz, 4H), 1.97 (m, 1H),1.84-1.81 (m, 2H), 1.23-1.21 (m, 2H) 516.4 221

12.75 (s, 1H), 10.98 (s, 1H), 8.45 (d, J = 2.5 Hz, 1H), 7.94 (dd, J₁ =2.4 Hz, J₂ = 9.3 Hz, 1H), 7.87 (s, 1H), 6.84 (d, J = 9.3 Hz, 1H), 3.79(t, J = 5.9 Hz, 2H), 3.70 (t, J = 5.7 Hz, 2H), 3.37-3.35 (m, 4H), 2.78(m, 4H), 1.73 (m, 4H), 1.50 (m, 4H) 422.1 222

12.80 (s, 1H), 1.58 (s, 1H), 8.08 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 8.3Hz, 2H), 7.91 (s, 1H), 5.09 (t, J = 5.4 Hz, 1H), 4.75 (t, J = 4.9 Hz,2H), 3.97-3.96 (m, 2H), 3.83 (t, J = 6.4 Hz, 4H), 1.84-1.76 (m, 4H),1.53 (m, 4H) 449.3 223

12.76 (s, 1H), 11.15 (s, 1H), 7.88 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H),7.01 (d, J = 8.8 Hz, 2H), 5.46 (s, 1H), 4.90-4.60 (m, 2H), 4.10-3.60 (m,4H), 3.30-3.10 (m, 4H), 3.02- 2.96 (m, 2H), 2.55-2.52 (m, 4H), 1.98 (m,1H), 1.84-1.81 (m, 2H), 1.34 (s, 6H) 477.2 224

12.78 (s, 1H), 11.17 (s, 1H), 7.89 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H),7.02 (d, J = 7.8 Hz, 2H), 4.79-4.68 (m, 2H), 4.20-4.00 (m, 4H), 3.02-2.96 (m, 2H), 2.55-2.53 (m, 4H), 1.98-1.91 (m, 1H), 1.84-1.81 (m, 2H),1.24-1.08 (m, 10H) 225

— 433.4 226

12.70 (s, 1H), 11.58 (s, 1H), 8.11 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.8Hz, 2H), 7.84 (s, 1H), 5.00-4.80 (m, 2H), 4.73 (q, J = 7.3 Hz, 2H),3.10-2.95 (m, 2H), 2.47 (d, J = 6.4 Hz, 2H), 2.10-1.93 (m, 3H), 1.66 (t,J = 7.4 Hz, 3H), 1.36-1.34 (m, 2H) 458.3 227

12.82 (s, 1H), 11.61 (s, 1H), 8.07 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.8Hz, 2H), 7.93 (s, 1H), 3.83 (q, J = 6.4 Hz, 4H), 1.84-1.77 (m, 4H), 1.53(m, 4H) 403.2 (M − 1) 228

12.76 (s, 1H), 10.97 (s, 1H), 8.42 (d, J = 2.4 Hz, 1H), 7.90-7.87 (m,2H), 6.90 (d, J = 9.3 Hz, 1H), 4.58- 4.49 (m, 2H), 3.46 (m, 4H), 3.00-2.94 (m, 2H), 2.54-2.53 (m, 2H), 2.39 (m, 6H), 1.97-1.95 (m, 1H),1.83-1.80 (m, 2H), 1.25-1.19 (m, 2H), 1.05 (t, J = 7.1 Hz, 3H)   476(M + 2) 229

12.71 (s, 1H), 11.00 (s, 1H), 8.46 (d, J = 2.9 Hz, 1H), 7.96 (dd, J₁ =2.8 Hz, J₂ = 9.1 Hz, 1H), 7.87 (s, 1H), 6.88 (d, J = 9.3 Hz, 1H), 3.79(t, J = 6.1 Hz, 2H), 3.70 (t, J = 5.6 Hz, 2H), 3.45 (t, J = 4.9 Hz, 4H),2.45 (t, J = 4.9 Hz, 4H), 2.36 (q, J = 7.3 Hz, 2H), 1.74 (m, 4H), 1.50(m, 4H), 1.04 (t, J = 7.1 Hz, 3H) 450.0 230

12.80 (bs, 1H), 11.17 (s, 1H), 7.90 (s, 1H), 7.61 (d, J = 8.3 Hz, 1H),6.99 (d, J = 8.3 Hz, 2H), 4.07 (t, J = 5.6 Hz, 2H), 3.87 (m, 4H), 3.81(m, 2H), 2.72 (t, J = 4.2 Hz, 4H), 2.66 (t, J = 5.7 Hz, 2H), 2.55 (m,4H), 2.42 (m, 4H) 491.1 231

12.80 (bs, 1H), 10.96 (s, 1H), 8.41 (d, J = 2.4 Hz, 1H), 7.87 (s, 1H),7.86-7.85 (m, 1H), 6.86 (d, J = 9.3 Hz, 1H), 4.48-4.61 (m, 2H), 2.99-2.93 (m, 2H), 2.78 (m, 4H), 2.54- 2.53 (m, 6H), 1.96-1.95 (m, 1H),1.83-1.80 (m, 2H), 1.24-1.19 (m, 2H) 445.2 (M − 1) 232

12.70 (s, 1H), 10.96 (s, 1H), 8.41 (d, J = 2.4 Hz, 1H), 7.94 (dd, J₁ =2.4 Hz, J₂ = 8.8 Hz, 1H), 7.86 (s, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.17-4.10 (m, 2H), 3.79 (t, J = 5.9 Hz, 2H), 3.70 (t, J = 5.9 Hz, 2H), 2.83-2.77 (m, 2H), 2.61-2.50 (m, 2H), 2.28-2.11 (m, 2H), 1.90-1.86 (m, 1H),1.83-1.65 (m, 6H), 1.50-1.42 (m, 4H) 479.3 233

12.71 (s, 1H), 11.16 (s, 1H), 7.85 (s, 1H), 7.59 (d, J = 9.3 Hz, 2H),6.92 (d, J = 8.8 Hz, 2H), 3.80 (t, J = 5.9 Hz, 2H), 3.75 (t, J = 6.1 Hz,2H), 3.70-3.55 (m, 3H), 1.90-1.60 (m, 10H), 1.51 (m, 6H) 478.2 234

12.72 (s, 1H), 11.01 (s, 1H), 8.49 (d, J = 2.5 Hz, 1H), 7.99 (dd, J₁ =2.7 Hz, J₂ = 9.1 Hz, 1H), 7.87 (s, 1H), 6.94 (d, J = 8.8 Hz, 1H), 4.10(s, 2H), 3.79 (t, J = 5.9 Hz, 2H), 3.71 (t, J = 6.1 Hz, 2H), 3.59-3.47(m, 8H), 1.74 (m, 4H), 1.50 (m, 4H) 489.3 235

12.80 (s, 1H), 11.55 (s, 1H), 8.06 (d, J = 8.8 Hz, 2H), 7.95 (d, J = 8.8Hz, 2H), 7.90 (s, 1H), 5.15 (s, 2H), 3.84-3.78 (m, 4H), 1.83-1.76 (m,4H), 1.52 (m, 4H) 461.3 (M − 1) 236

12.70 (s, 1H), 10.97 (s, 1H), 8.42 (d, J = 3.0 Hz, 1H), 7.92 (dd, J₁ =2.8 Hz, J₂ = 9.1 Hz, 1H), 7.86 (s, 1H), 6.86 (d, J = 9.3 Hz, 1H), 4.36(t, J = 5.2 Hz, 1H), 4.25-4.21 (m, 2H), 3.79 (t, J = 6.2 Hz, 2H), 3.70(t, J = 5.9 Hz, 2H), 3.47 (q, J = 6.2 Hz, 2H), 2.77-2.74 (m, 2H), 1.73-1.71 (m, 6H), 1.64-1.59 (m, 1H), 1.50 (m, 4H), 1.38 (q, J = 6.3 Hz, 2H),1.14-1.10 (m, 2H) 465.3 237

12.77 (s, 1H), 10.98 (s, 1H), 8.45 (d, J = 2.5 Hz, 1H), 7.93 (dd, J₁ =2.7 Hz, J₂ = 9.1 Hz, 1H), 7.89 (s, 1H), 6.95 (d, J = 9.3 Hz, 1H), 4.79-4.61 (m, 2H), 4.11 (s, 2H), 3.60- 3.54 (m, 4H), 3.51-3.46 (m, 4H),3.00-2.94 (m, 2H), 2.55-2.53 (m, 2H), 1.97-1.94 (m, 1H), 1.83-1.80 (m,2H), 1.23-1.17 (m, 2H) 512.4 (M − 1) 238

— 508.4 239

12.71 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 4.40 (bs, 1H), 4.05 (t, J = 5.9 Hz, 2H), 3.80(t, J = 6.1 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.48 (t, J = 6.2 Hz, 2H),2.67 (t, J = 5.6 Hz, 2H), 2.54 (m, 4H), 2.42-2.33 (m, 6H), 1.76 (m, 4H),1.51 (m, 4H) 509.3 240

12.76 (s, 1H), 11.16 (s, 1H), 7.88 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H),7.02 (d, J = 8.8 Hz, 2H), 4.78-4.71 (m, 2H), 4.10 (s, 2H), 3.61 (t, J =4.9 Hz, 2H), 3.50 (t, J = 4.9 Hz, 2H), 3.18 (t, J = 4.9 Hz, 2H), 3.13(t, J = 5.2 Hz, 2H), 3.02-2.96 (m, 2H), 2.55-2.52 (m, 2H), 1.98-1.95 (m,1H), 1.84-1.81 (m, 2H), 1.26- 1.23 (m, 2H) 513.4 241

12.90 (s, 1H), 11.90 (bs, 1H), 8.09 (d, J = 8.3 Hz, 2H), 7.95 (s, 1H),7.91 (d, J = 8.8 Hz, 2H), 4.94 (s, 2H), 4.80-4.77 (m, 2H), 3.06-3.00 (m,2H), 2.56-2.54 (m, 4H), 1.99 (m, 1H), 1.89-1.86 (m, 2H) 486.4 (M − 1)242

12.71 (s, 1H), 11.99 (s, 1H), 8.47 (d, J = 2.9 Hz, 1H), 7.95 (dd, J₁ =2.7 Hz, J₂ = 9.1 Hz, 1H), 7.87 (s, 1H), 6.88 (d, J = 9.3 Hz, 1H), 3.79(t, J = 6.1 Hz, 2H), 3.70 (t, J = 5.9 Hz, 2H), 3.45 (t, J = 4.7 Hz, 4H),2.40 (t, J = 4.9 Hz, 4H), 2.22 (s, 3H), 1.74 (m, 4H), 1.50 (m, 4H) 436.3243

12.76 (s, 1H), 10.97 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 7.88 (dd, J₁ =2.7 Hz, J₂ = 9.1 Hz, 1H), 7.87 (s, 1H), 6.90 (d, J = 8.8 Hz, 1H), 4.79-4.61 (m, 2H), 3.46 (t, J = 4.9 Hz, 4H), 3.00-2.94 (m, 2H), 2.54-2.53 (m,2H), 2.40 (t, J = 4.9 Hz, 4H), 2.22 (s, 3H), 1.98-1.95 (m, 1H),1.82-1.80 (m, 2H), 1.23-1.19 (m, 2H) 461.4 244

12.70 (s, 1H), 11.17 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 7.3 Hz, 2H),6.97 (m, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.67-3.64 (m, 2H), 2.89-2.87 (m, 2H), 2.67-2.59 (m, 2H), 1.89 (m, 1H),1.75-1.68 (m, 6H), 1.51 (m, 4H), 1.37-1.35 (m, 2H) 502.5 245

16.70 (s, 1H), 12.87 (s, 1H), 11.60 (s, 1H), 8.09 (d, J = 8.3 Hz, 2H),7.97 (d, J = 8.4 Hz, 2H), 7.94 (s, 1H), 4.82-4.74 (m, 2H), 3.06 (m, 2H),2.57-2.53 (m, 2H), 2.01-1.91 (m, 1H), 1.86 (m, 2H), 1.26-1.23 (m, 2H)428.3 (M − 1) 246

16.04 (bs, 1H), 12.75 (s, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.55 (d, J =9.3 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.78 (m, 2H), 3.69-3.66 (m, 2H),3.02-2.95 (m, 2H), 2.88- 2.86 (m, 2H), 2.67-2.60 (m, 2H), 2.55-2.30 (m,2H), 1.97-1.91 (m, 1H), 1.90-1.81 (m, 3H), 1.70-1.67 (m, 2H), 1.39-1.33(m, 2H), 1.24- 1.21 (m, 2H) 525.5 (M − 1) 247

— 435.5 248

12.75 (s, 1H), 11.13 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H),6.98 (d, J = 9.3 Hz, 2H), 4.78-4.73 (m, 2H), 3.13 (t, J = 4.7 Hz, 4H),3.02-2.95 (m, 2H), 2.55-2.52 (m, 2H), 2.47 (m, 4H), 2.24 (s, 3H),1.97-1.95 (m, 1H), 1.84-1.81 (m, 2H), 1.23-1.22 (m, 2H) 460.5 249

12.76 (s, 1H), 10.94 (s, 1H), 8.38 (d, J = 2.5 Hz, 1H), 7.89-7.86 (m,2H), 6.87 (d, J = 9.3 Hz, 1H), 4.78- 4.61 (m, 2H), 4.19-4.10 (m, 2H),3.00-2.94 (m, 2H), 2.65-2.55 (m, 2H), 2.54-2.53 (m, 2H), 2.45-2.28 (m,2H), 1.96-1.80 (m, 6H), 1.23- 1.19 (m, 4H) 504.5 250

12.74 (bs, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H),6.95 (d, J = 8.8 Hz, 2H), 4.78 (m, 2H), 3.62-3.55 (m, 2H), 3.01-2.95 (m,2H), 2.55-2.53 (m, 2H), 2.30- 2.09 (m, 2H), 1.98 (m, 2H), 1.84- 1.51 (m,6H), 1.12-1.09 (m, 2H) 503.4 251

12.77 (s, 1H), 10.98 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 7.92 (dd, J₁ =2.7 Hz, J₂ = 9.1 Hz, 1H), 7.88 (s, 1H), 6.93 (d, J = 9.3 Hz, 1H), 5.47(s, 1H), 4.54 (m, 2H), 4.06-4.00 (m, 2H), 3.50-3.47 (m, 4H), 3.00- 2.94(m, 2H), 2.55-2.52 (m, 4H), 2.00-1.94 (m, 1H), 1.83-1.80 (m, 2H), 1.34(s, 6H), 1.25-1.19 (m, 2H) 531.2 252

16.10 (bs, 1H), 12.71 (s, 1H), 10.98 (s, 1H), 8.43 (d, J = 2.4 Hz, 1H),7.94 (dd, J₁ = 2.7 Hz, J₂ = 9.1 Hz, 1H), 7.87 (s, 1H), 6.88 (d, J = 9.3Hz, 1H), 4.26-4.23 (m, 2H), 3.79 (t, J = 5.9 Hz, 2H), 3.70 (t, J = 5.9Hz, 2H), 2.85 (d, J = 6.9 Hz, 2H), 2.79-2.73 (m, 2H), 2.00-1.95 (m, 1H),1.73-1.65 (m, 6H), 1.50 (m, 4H), 1.23-1.21 (m, 2H) 503.6 253

16.04 (bs, 1H), 12.76 (s, 1H), 10.95 (s, 1H), 8.39 (d, J = 2.9 Hz, 1H),7.88 (s, 1H), 7.87 (dd, J₁ = 2.7 Hz, J₂ = 9.1 Hz, 1H), 6.90 (d, J = 9.3Hz, 1H), 4.79-4.62 (m, 2H), 4.27-4.24 (m, 2H), 3.00-2.94 (m, 2H),2.87-2.85 (m, 2H), 2.80-2.74 (m, 2H), 2.54-2.53 (m, 4H), 2.01- 1.95 (m,2H), 1.82-1.80 (m, 2H), 1.82-1.80 (m, 2H), 1.68-1.65 (m, 2H), 1.28-1.19(m, 4H) 528.5 254

12.76 (s, 1H), 11.19 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H),6.99 (d, J = 9.3 Hz, 2H), 4.42-4.40 (m, 1H), 3.80 (t, J = 5.9 Hz, 2H),3.74 (t, J = 5.9 Hz, 2H), 3.13 (s, 2H), 2.95-2.92 (m, 2H), 2.67-2.62 (m,2H), 2.46-2.40 (m, 2H), 1.98 (m, 2H), 1.75-1.70 (m, 6H), 1.51 (m, 4H)494.3 255

12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H),6.95 (d, J = 9.3 Hz, 2H), 3.80 (t, J = 6.0 Hz, 2H), 3.75 (t, J = 5.9 Hz,2H), 3.47 (t, J = 5.6 Hz, 2H), 3.25 (s, 3H), 3.11 (m, 4H), 2.56 (m, 6H),1.78-1.74 (m, 4H), 1.51 (m, 4H) 479.0 256

12.76 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 9.3 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 4.78-4.71 (m, 2H), 3.48 (t, J = 5.7 Hz, 2H),3.12 (s, 3H), 3.07-2.96 (m, 6H), 2.55-2.53 (m, 8H), 1.98-1.97 (m, 1H),1.84-1.81 (m, 2H), 1.23-1.20 (m, 2H) 504.2 257

11.14 (s, 1H), 7.87 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8Hz, 2H), 3.98 (m, 2H), 3.12 (m, 4H), 3.07 (m, 2H), 3.07-2.95 (m, 2H),2.67-2.64 (m, 2H), 2.55-2.53 (m, 4H), 2.37-2.33 (m, 2H), 1.97 (m, 1H),1.84-1.81 (m, 2H), 1.23- 1.20 (m, 2H) 489.4 258

12.70 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 9.3 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 4.41 (t, J = 5.2 Hz, 1H), 3.80 (t, J = 6.2 Hz,2H), 3.75 (t, J = 5.9 Hz, 2H), 3.56- 3.38 (m, 1H), 3.36-3.35 (m, 2H),3.30-3.23 (m, 1H), 3.13-3.05 (m, 2H), 1.78-1.66 (m, 5H), 1.51 (m, 6H),1.37-1.27 (m, 1H), 0.89-0.82 (m, 1H), 0.48-0.45 (m, 1H), 0.17- 0.15 (m,1H) 476.4 259

12.75 (s, 1H), 11.13 (s, 1H), 7.88 (s, 1H), 7.55 (d, J = 9.3 Hz, 2H),6.99 (d, J = 9.3 Hz, 2H), 4.76 (m, 2H), 4.41 (t, J = 5.4 Hz, 1H), 3.56-3.51 (m, 1H), 3.37-3.34 (m, 1H), 3.30-3.25 (m, 1H), 3.14-3.06 (m, 2H),3.02-2.96 (m, 2H), 2.55-2.53 (m, 2H), 1.97-1.96 (m, 1H), 1.84- 1.81 (m,2H), 1.72-1.68 (m, 1H), 1.54-1.47 (m, 2H), 1.36-1.09 (m, 4H), 0.88-0.82(m, 1H), 0.48-0.45 (m, 1H), 0.18-0.15 (m, 1H) 501.2 260

12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H),6.96 (d, J = 9.3 Hz, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz,2H), 3.46 (t, J = 6.1 Hz, 2H), 3.12 (m, 4H), 2.41-2.38 (m, 2H), 1.77-1.74 (m, 4H), 1.63-1.60 (m, 2H), 1.51 (m, 4H) 479.4 261

12.76 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 9.3 Hz, 2H),6.98 (d, J = 8.8 Hz, 2H), 4.78-4.71 (m, 2H), 3.46 (t, J = 6.4 Hz, 2H),3.13 (m, 4H), 3.02-2.95 (m, 2H), 2.55-2.53 (m, 6H), 2.42-2.38 (m, 2H),1.97-1.96 (m, 1H), 1.84-1.81 (m, 2H), 1.65-1.58 (m, 2H), 1.23- 1.22 (m,2H) 504.4 262

12.78 (s, 1H), 11.17 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H),7.02 (d, J = 8.8 Hz, 2H), 4.45-4.44 (m, 2H), 4.43 (m, 1H), 3.22 (s, 2H),3.02-2.96 (m, 4H), 2.74-2.67 (m, 2H), 2.67 (t, J = 1.8 Hz, 2H),2.55-2.54 (m, 2H), 2.03-2.00 (m, 3H), 1.84-1.81 (m, 2H), 1.77-1.73 (m,2H) 519.4 263

12.67 (s, 1H), 11.08 (s, 1H), 7.84 (s, 1H), 7.55 (d, J = 9.3 Hz, 2H),6.70 (d, J = 8.8 Hz, 2H), 4.39 (m, 1H), 3.79 (t, J = 6.1 Hz, 25H), 3.74(t, J = 5.9 Hz, 2H), 3.49-3.42 (m, 6H), 2.79 (m, 2H), 2.62-2.56 (m, 4H),1.87 (t, J = 5.1 Hz, 2H), 1.77- 1.74 (m, 4H), 1.51 (m, 4H) 479.4 264

12.73 (s, 1H), 11.06 (s, 1H), 7.86 (s, 1H), 7.50 (d, J = 9.3 Hz, 2H),6.73 (d, J = 8.8 Hz, 2H), 4.76 (m, 2H), 4.73 (m, 1H), 3.49 (m, 4H), 3.45(t, J = 6.1 Hz, 2H), 3.00-2.94 (m, 2H), 2.80 (m, 2H), 2.59-2.53 (m, 6H),1.97-1.94 (m, 1H), 1.88- 1.81 (m, 4H), 1.23-1.21 (m, 2H) 504.4 265

12.69 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H),6.93 (d, J = 8.8 Hz, 2H), 4.28 (m, 1H), 3.80 (t, J = 5.9 Hz, 2H), 3.75(t, J = 5.9 Hz, 2H), 3.09 (m, 4H), 2.70 (m, 4H), 1.77-1.74 (m, 4H), 1.51(m, 4H), 1.23 (s, 6H) 493.5 266

12.75 (s, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 9.3 Hz, 2H),6.95 (d, J = 8.8 Hz, 2H), 4.72 (m, 2H), 4.27 (m, 1H), 3.09 (m, 4H),3.02-2.95 (m, 2H), 2.69-2.68 (m, 4H), 2.55-2.53 (m, 2H), 1.99-1.95 (m,1H), 1.84-1.81 (m, 2H), 1.34- 1.17 (m, 4H), 0.98 (s, 6H) 518.2 267

— 492.5 268

12.75 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H),6.97 (d, J = 8.8 Hz, 2H), 3.12-3.11 (m, 4H), 3.02-2.95 (m, 2H), 2.55-2.53 (m, 6H), 2.23 (s, 6H), 1.99- 1.97 (m, 1H), 1.84-1.81 (m, 2H),1.34-1.23 (m, 6H) 517.5 269

12.72 (s, 1H), 11.19 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H),6.95 (d, J = 9.3 Hz, 2H), 4.80 (s, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.74(t, J = 5.9 Hz, 2H), 3.46 (m, 6H), 2.33-2.32 (m, 4H), 1.76 (m, 4H), 1.51(m, 4H), 1.01 (t, J = 7.1 Hz, 3H) 507.3 270

— 532.4 271

12.77 (s, 1H), 11.16 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 7.8 Hz, 2H),6.97 (d, J = 8.3 Hz, 2H), 4.81 (s, 2H), 4.69 (m, 2H), 3.51-3.46 (m, 6H),2.99 (m, 2H), 2.67 (m, 2H), 2.34-2.27 (m, 4H), 2.19 (s, 3H), 1.99-1.91(m, 1H), 1.84-1.81 (m, 2H) 518.4 272

12.69 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 9.2 Hz, 2H),6.95 (d, J = 8.8 Hz, 2H), 4.41 (t, J = 5.1 Hz, 1H), 3.80 (t, J = 6.1 Hz,2H), 3.75 (t, J = 5.9 Hz, 2H), 3.59- 3.56 (m, 2H), 3.52-3.47 (m, 2H),1.77-1.69 (m, 8H), 1.51-1.42 (m, 8H) 464.5 273

12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H),6.95 (d, J = 9.3 Hz, 2H), 4.44 (m, 1H), 3.80 (t, J = 6.2 Hz, 2H), 3.75(t, J = 5.9 Hz, 2H), 3.65 (d, J = 5.4 Hz, 1H), 3.35-3.33 (m, 2H), 3.12(t, J = 4.4 Hz, 4H), 2.59-2.53 (m, 4H), 2.46-2.42 (m, 2H), 2.33-2.27 (m,1H), 1.78-1.74 (m, 4H), 1.51 (m, 4H) 495.2 274

12.75 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 9.3 Hz, 2H),6.98 (d, J = 8.8 Hz, 2H), 4.71 (m, 2H), 4.45 (m, 1H), 3.65 (m, 1H),3.35-3.33 (m, 2H), 3.13 (m, 4H), 3.02-2.96 (m, 2H), 2.60 (m, 4H),2.52-2.51 (m, 2H), 2.46-2.45 (m, 2H), 2.33-2.01 (m, 1H), 1.99-1.95 (m,1H), 1.84-1.81 (m, 2H), 1.23- 1.21 (m, 2H) 520.4 275

12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H),6.96 (d, J = 8.8 Hz, 2H), 4.64 (t, J = 4.9 Hz, 1H), 4.52 (t, J = 4.9 Hz,1H), 3.80 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.13 (t, J =4.9 Hz, 4H), 2.71 (t, J = 4.9 Hz, 1H), 2.64 (t, J = 4.9 Hz, 1H), 2.60(t, J = 4.7 Hz, 4H), 1.78-1.74 (m, 4H), 1.51 (m, 4H) 467.3 276

12.75 (s, 1H), 11.14 (s, 1H), 7.87 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H),6.98 (d, J = 8.8 Hz, 2H), 4.77-4.71 (m, 2H), 4.64 (t, J = 4.9 Hz, 1H),4.52 (t, J = 4.9 Hz, 1H), 3.14 (t, J = 4.9 Hz, 4H), 3.02-2.95 (m, 2H),2.71 (t, J = 4.4 Hz, 1H), 2.67 (t, J = 2.0 Hz, 1H), 2.64 (t, J = 4.9 Hz,4H), 2.60-2.53 (m, 2H), 1.98-1.95 (m, 1H), 1.84-1.82 (m, 2H), 1.23- 1.21(m, 2H) 492.4 277

12.70 (s, 1H), 10.96 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 7.92 (dd, J1 =2.4 Hz, J2 = 9.3 Hz, 1H), 7.87 (s, 1H), 6.85 (d, J = 9.3 Hz, 2H), 4.82(d, J = 4.4 Hz, 1H), 4.16-4.13 (m, 1H), 3.95-3.92 (m, 1H), 3.79 (t, J =6.1 Hz, 2H), 3.70 (t, J = 4.9 Hz, 2H), 3.51-3.48 (m, 1H), 1.73 (m, 6H),1.50-1.33 (m, 8H) 437.4 278

— 437.4 279

12.70 (s, 1H), 11.18 (s, 1H), 7.86 (s, 1H), 7.64 (d, J = 9.3 Hz, 2H),7.92 (d, J = 8.9 Hz, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.75 (t, J = 5.9 Hz,2H), 3.32-3.30 (m, 4H), 2.10-2.01 (m, 4H), 1.78-1.75 (m, 4H), 1.51 (m,4H) 456.2 280

12.76 (s, 1H), 11.16 (s, 1H), 7.88 (s, 1H), 7.59 (d, J = 8.8 Hz, 2H),7.05 (d, J = 9.3 Hz, 2H), 4.80-4.60 (m, 2H), 3.34-3.31 (m, 4H), 3.02-2.96 (m, 2H), 2.55-2.53 (m, 2H), 2.11-2.01 (m, 4H), 1.99-1.97 (m, 1H),1.84-1.81 (m, 2H), 1.23-1.21 (m, 2H) 479.1 281

— 436.3 282

— 461.5 283

12.72 (s, 1H), 11.19 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 8.8 Hz, 2H),6.95 (d, J = 8.8 Hz, 2H), 4.80 (s, 2H), 3.80 (t, J = 5.9 Hz, 2H), 3.74(t, J = 5.9 Hz, 2H), 3.45 (m, 4H), 2.46-2.26 (m, 4H), 2.18 (s, 3H), 1.76(m, 4H), 1.51 (m, 4H) 493.2 284

12.75 (s, 1H), 11.13 (s, 1H), 7.88 (s, 1H), 7.87 (s, 1H), 7.55 (d, J =9.3 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.72 (m, 2H), 4.53 (t, J = 5.2Hz, 1H), 3.68-3.57 (m, 2H), 3.36- 3.34 (m, 2H), 3.01-2.95 (m, 2H),2.66-2.60 (m, 1H), 2.55-2.53 (m, 2H), 2.43-2.38 (m, 1H), 1.96-1.94 (m,1H), 1.84-1.82 (m, 2H), 1.73- 1.71 (m, 4H), 1.59-1.54 (m, 1H), 1.23-1.21(m, 2H) 475.6 285

12.69 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H),6.94 (d, J = 8.8 Hz, 2H), 4.53 (m, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.75(t, J = 5.9 Hz, 2H), 3.69-3.54 (m, 2H), 2.67-2.53 (m, 1H), 2.46-2.33 (m,1H), 1.78-1.71 (m, 8H), 1.57 (m, 1H), 1.51 (m, 4H), 1.23 (m, 2H) 450.3286

12.75 (s, 1H), 11.13 (s, 1H), 7.55 (d, J = 9.3 Hz, 2H), 6.97 (d, J = 8.8Hz, 2H), 4.80 (m, 2H), 4.41 (t, J = 5.1 Hz, 1H), 3.60-3.53 (m, 4H), 2.99(m, 2H), 2.55-2.53 (m, 4H), 2.0 (m, 1H), 1.85-1.69 (m, 6H), 1.34-1.22(m, 4H) . 489.4 287

12.75 (s, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H),6.98 (d, J = 9.3 Hz, 2H), 4.90-4.60 (m, 2H), 3.50-3.45 (m, 2H), 3.35-3.33 (m, 1H), 3.27 (s, 3H), 3.01- 2.84 (m, 4H), 2.55-2.52 (m, 2H),1.98-1.81 (m, 5H), 1.56-1.48 (m, 2H), 1.23-1.21 (m, 2H) 475.2 288

12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H),6.97 (d, J = 7.3 Hz, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz,2H), 3.48-3.44 (m, 3H), 3.27 (s, 3H), 2.87 (m, 2H), 1.95-1.93 (m, 2H),1.77-1.74 (m, 4H), 1.51 (m, 6H) 450.4 289

12.70 (s, 1H), 11.16 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 9.3 Hz, 2H),6.99 (d, J = 9.3 Hz, 2H), 4.89-4.77 (m, 1H), 3.80 (t, J = 6.2 Hz, 2H),3.75 (t, J = 5.9 Hz, 2H), 3.36-3.35 (m, 2H), 3.13-3.07 (m, 2H), 2.00-1.92 (m, 2H), 1.82-1.75 (m, 6H), 1.51 (m, 4H) 438.0 290

12.75 (s, 1H), 11.14 (s, 1H), 7.88 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H),7.01 (d, J = 9.3 Hz, 2H), 4.92-4.75 (m, 3H), 3.37-3.34 (m, 2H), 3.15-3.09 (m, 2H), 3.02-2.96 (m, 2H), 2.55-2.52 (m, 4H), 2.03-1.92 (m, 3H),1.84-1.74 (m, 4H), 1.24-1.21 (m, 2H) 463.4 291

12.78 (s, 1H), 11.19 (s, 1H), 7.90 (s, 1H), 7.64 (d, J = 8.8 Hz, 2H),7.06 (d, J = 6.9 Hz, 2H), 5.30 (m, 1H), 4.90-4.70 (m, 2H), 4.50 (m, 1H),3.73 (m, 2H), 3.30-2.96 (m, 6H), 2.56-2.54 (m, 4H), 2.20-2.16 (m, 2H),1.98-1.81 (m, 5H) 505.2 292

12.75 (s, 1H), 11.23 (s, 1H), 8.64 (s, 2H), 7.90 (s, 1H), 7.70 (d, J =8.8 Hz, 2H), 7.04 (d, J = 9.3 Hz, 2H), 4.64-4.61 (m, 1H), 3.81 (t, J =6.1 Hz, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.39-3.37 (m, 2H), 3.24-3.08 (m,2H), 2.12-2.07 (m, 2H), 1.84- 1.76 (m, 6H), 1.51 (m, 4H) 436.4 293

12.70 (s, 1H), 11.15 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H),6.99 (d, J = 9.3 Hz, 2H), 4.86 (t, J = 5.4 Hz, 1H), 4.80-4.69 (m, 2H),3.99 (t, J = 5.1 Hz, 2H), 3.72 (t, J = 5.1 Hz, 2H), 3.02-2.95 (m, 2H),2.55-2.53 (m, 2H), 1.97 (m, 1H), 1.84-1.81 (m, 2H), 1.24 (m, 2H) 420.3(M − 1) 294

12.71 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 9.3 Hz, 2H),6.97 (d, J = 9.3 Hz, 2H), 4.85 (t, J = 5.6 Hz, 1H), 3.99 (t, J = 4.9 Hz,2H), 3.80 (t, J = 6.1 Hz, 2H), 3.76- 3.69 (m, 4H), 1.76 (m, 4H), 1.51(m, 4H) 397.2 295

12.76 (s, 1H), 11.20 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H),6.97 (d, J = 9.3 Hz, 2H), 4.73 (m, 2H), 4.54 (m, 1H), 4.04 (t, J = 6.4Hz, 2H), 3.56 (t, J = 6.1 Hz, 2H), 3.01-2.95 (m, 2H), 2.55-2.53 (m, 2H),1.99-1.89 (m, 1H), 1.87-1.81 (m, 4H), 1.23-1.21 (m, 2H) 436.4 296

12.71 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H),6.95 (d, J = 9.3 Hz, 2H), 4.54 (t, J = 5.4 Hz, 1H), 4.03 (t, J = 6.4 Hz,2H), 3.80 (t, J = 5.9 Hz, 2H), 3.74 (t, J = 5.9 Hz, 2H), 3.58-3.54 (m,2H), 1.86 (t, J = 6.4 Hz, 2H), 1.76 (m, 4H), 1.51 (m, 4H) 411.3 297

12.72 (s, 1H), 11.05 (s, 1H), 7.86 (s, 3H), 7.49 (d, J = 8.8 Hz, 2H),6.73 (d, J = 8.8 Hz, 2H), 4.75 (m, 2H), 3.51 (t, J = 5.4 Hz, 4H), 3.29(m, 2H), 3.00-2.67 (m, 5H), 2.55- 2.53 (m, 2H), 1.97-1.94 (m, 1H),1.83-1.81 (m, 4H), 1.23-1.21 (m, 4H), 1.00 (s, 6H) 532.3 298

12.69 (s, 1H), 11.15 (s, 1H), 7.86 (s, 1H), 7.61 (d, J = 9.3 Hz, 2H),6.95 (d, J = 8.8 Hz, 2H), 4.60 (t, J = 5.9 Hz, 1H), 4.48 (t, J = 5.9 Hz,1H), 3.80 (t, J = 6.1 Hz, 2H), 3.76 (t, J = 5.9 Hz, 2H), 3.67-3.64 (m,2H), 2.66-2.59 (m, 2H), 1.78-1.76 (m, 6H), 1.64-1.58 (m, 3H), 1.51 (m,4H), 1.31-1.23 (m, 2H) 466.4 299

12.75 (s, 1H), 11.13 (s, 1H), 7.87 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H),6.97 (d, J = 9.3 Hz, 2H), 4.77-4.71 (m, 2H), 4.60 (t, J = 6.1 Hz, 1H),4.48 (t, J = 5.9 Hz, 1H), 3.68-3.65 (m, 2H), 3.01-2.95 (m, 2H), 2.67-2.60 (m, 2H), 2.55-2.53 (m, 2H), 1.98-1.95 (m, 1H), 1.84-1.76 (m, 4H),1.67 (q, J = 6.4 Hz, 1H), 1.62- 1.52 (m, 2H), 1.34-1.21 (m, 4H) 300

12.81 (s, 1H), 11.37 (s, 1H), 7.90 (s, 1H), 6.96 (d, J = 2.4 Hz, 1H),6.27 (t, J = 2.2 Hz, 1H), 3.76 (s, 6H), 3.03 (m, 2H), 2.55-2.53 (m, 2H),1.99-1.96 (m, 1H), 1.84-1.81 (m, 2H), 1.25-1.23 (m, 2H) 422.3 301

12.83 (s, 1H), 11.44 (s, 1H), 7.92 (s, 1H), 7.86-7.82 (m, 2H), 7.42 (d,J = 8.3 Hz, 2H), 4.80-4.67 (m, 2H), 3.02 (m, 2H), 2.56-2.53 (m, 2H),2.00-1.96 (m, 1H), 1.86-1.84 (m, 2H), 1.25-1.23 (m, 2H) 446.3 302

12.76 (s, 1H), 11.43 (s, 1H), 7.89 (s, 1H), 6.99 (d, J = 1.9 Hz, 2H),6.26 (t, J = 2.2 Hz, 1H), 3.80 (q, J = 5.4 Hz, 4H), 3.76 (m, 6H), 1.76(s, 6H), 1.76 (m, 4H), 1.51 (m, 4H) 379.3 303

12.78 (s, 1H), 11.45 (s, 1H), 7.91 (s, 1H), 7.89 (d, J = 9.3 Hz, 2H),7.40 (d, J = 8.3 Hz, 2H), 3.82 (q, J = 6.1 Hz, 2H), 3.76 (t, J = 5.9 Hz,2H), 1.77 (t, J = 5.6 Hz, 4H), 1.51 (m, 4H) 421.3 304

12.73 (s, 1H), 11.31 (s, 1H), 7.88 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H),7.24 (d, J = 8.3 Hz, 2H), 3.81 (t, J = 6.1 Hz, 2H), 3.76 (t, J = 5.9 Hz,2H), 2.81 (t, J = 7.6 Hz, 2H), 2.55- 2.53 (m, 2H), 1.79-1.75 (m, 4H),1.51 (m, 4H) 409.5 305

12.79 (s, 1H), 11.29 (s, 1H), 7.90 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H),7.27 (d, J = 8.3 Hz, 2H), 4.90-4.60 (m 2H), 3.02 (m, 2H), 2.82 (t, J =7.3 Hz, 2H), 2.56-2.53 (m, 4H), 1.98-1.97 (m, 1H), 1.85-1.82 (m, 2H),1.23 (m, 2H) 434.0 306

12.67 (s, 1H), 11.05 (s, 1H), 7.84 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H),6.70 (d, J = 8.8 Hz, 2H), 4.73 (t, J = 5.4 Hz, 2H), 3.79 (t, J = 5.9 Hz,2H), 3.74 (t, J = 5.9 Hz, 2H), 3.56- 3.52 (m, 4H), 3.42-3.39 (m, 4H),1.75 (t, J = 4.4 Hz, 4H), 1.51 (m, 4H) 440.4 307

12.72 (s, 1H), 11.03 (s, 1H), 7.86 (s, 1H), 7.48 (d, J = 8.8 Hz, 2H),6.72 (d, J = 9.3 Hz, 2H), 4.75-4.42 (m, 4H), 3.57-3.52 (m, 4H), 3.43-3.40 (m, 4H), 3.00-2.97 (m, 2H), 2.55-2.52 (m, 2H), 2.00-1.90 (m, 1H),1.84-1.81 (m, 2H), 1.23-1.22 (m, 2H) 465.3 308

12.73 (s, 1H), 11.30 (s, 1H), 7.87 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H),7.20 (d, J = 8.8 Hz, 2H), 4.45 (t, J = 5.2 Hz, 1H), 3.80 (t, J = 6.2 Hz,2H), 3.75 (t, J = 5.9 Hz, 2H), 3.42 (q, J = 7.9 Hz, 2H), 1.78-1.70 (m,6H), 1.51 (m, 4H) 395.3 309

12.76 (s, 1H), 11.28 (s, 1H), 7.90 (s, 1H), 7.62 (d, J = 8.3 Hz, 2H),7.24 (d, J = 8.4 Hz, 2H), 4.80-4.60 (m, 2H), 4.46 (t, J = 5.6 Hz, 1H),3.42 (q, J = 6.4 Hz, 2H), 3.04-3.01 (m, 2H), 2.60 (t, J = 7.6 Hz, 2H),2.55-2.52 (m, 2H), 1.99-1.96 (m, 1H), 1.85-1.82 (m, 2H), 1.76-1.69 (m,2H), 1.23-1.22 (m, 2H) 420.3 310

12.76 (s, 1H), 11.39 (s, 1H), 7.89 (s, 1H), 7.86 (s, 1H), 7.59-7.57 (m,1H), 7.33 (t, J = 7.8 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 5.21 (t, J =5.6 Hz, 1H), 4.52 (d, J = 5.9 Hz, 2H), 3.83-3.78 (m, 4H), 1.80-1.76 (m,4H), 1.52 (m, 4H) 367.3 311

12.81 (s, 1H), 11.35 (s, 1H), 7.91 (s, 1H), 7.86 (s, 1H), 7.51 (d, J =9.3 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H), 7.05 (d, J = 7.3 Hz, 1H), 5.24(t, J = 5.9 Hz, 1H), 4.79 (m, 2H), 4.53 (d, J = 5.9 Hz, 2H), 3.04-2.98(m, 2H), 2.56-2.52 (m, 2H), 1.99- 1.98 (m, 1H), 1.86-1.82 (m, 2H), 1.23(m, 2H) 392.3 312

12.79 (s, 1H), 11.30 (s, 1H), 7.89 (s, 1H), 7.64 (d, J = 8.3 Hz, 2H),7.26 (d, J = 8.3 Hz, 2H), 4.79-4.70 (m, 2H), 4.52 (t, J = 5.8 Hz, 1H),4.40 (t, J = 5.9 Hz, 1H), 3.00 (m, 2H), 2.67 (t, J = 7.6 Hz, 2H), 2.55-2.54 (m, 2H), 2.09-1.89 (m, 3H), 1.85-1.82 (m, 2H), 1.24 (m, 2H) 420.3313

12.74 (s, 1H), 11.29 (s, 1H), 7.88 (s, 1H), 7.79-7.76 (m, 2H), 7.25-7.20 (m, 2H), 3.80 (t, J = 6.1 Hz, 2H), 3.73 (t, J = 5.9 Hz, 2H), 1.76-1.75 (m, 4H), 1.50 (m, 4H) 355.4 314

12.72 (s, 1H), 11.25 (s, 1H), 7.87 (s, 1H), 7.66 (d, J = 8.3 Hz, 2H),7.03 (d, J = 8.8 Hz, 2H), 4.87 (t, J = 5.9 Hz, 1H), 3.80 (t, J = 6.1 Hz,2H), 3.74 (t, J = 6.1 Hz, 2H), 3.38 (d, J = 5.9 Hz, 2H), 1.75 (m, 4H),1.51 (m, 4H), 1.19 (m, 6H) 425.3 315

12.78 (s, 1H), 11.24 (s, 1H), 7.89 (s, 1H), 7.62-7.60 (m, 2H), 7.05 (dd,J₁ = 2.0, J₂ = 6.9 Hz, 2H), 4.88 (t, J = 5.6 Hz, 1H), 4.80-4.60 (m, 2H),3.38 (d, J = 5.9 Hz, 2H), 2.99 (m, 2H), 2.55-2.53 (m, 2H), 1.99 (m, 1H),1.85-1.82 (m, 2H), 1.24- 1.23 (m, 2H), 1.19 (s, 6H) 449.1 316

13.00 (s, 1H), 12.72 (s, 1H), 11.20 (s, 1H), 7.87 (s, 1H), 7.65 (d, J =8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 3.80 (t, J = 5.9 Hz, 2H), 3.73(t, J = 5.9 Hz, 2H), 1.75-1.74 (m, 4H), 1.50 (m, 10H) 437.2 317

12.76 (s, 1H), 11.18 (s, 1H), 7.87 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H),6.89 (d, J = 8.8 Hz, 2H), 4.78-4.66 (m, 2H), 3.01-2.95 (m, 2H), 2.55-2.53 (m, 2H), 2.00-1.93 (m, 1H), 1.84-1.81 (m, 2H), 1.51 (s, 6H),1.26-1.18 (m, 2H) 462.2 (M − 1) 318

12.72 (s, 1H), 12.28 (s, 1H), 7.87 (s, 1H), 7.54 (d, J = 2.5 Hz, 1H),7.16 (dd, J₁ = 2.4 Hz, J₂ = 8.8 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 3.82-3.80 (m, 4H), 3.79 (s, 3H), 3.75 (s, 3H), 1.75 (m, 4H), 1.51 (m, 4H)397.2 319

12.78 (s, 1H), 11.22 (s, 1H), 7.89 (s, 1H), 7.56 (d, J = 4.4 Hz, 1H),7.08 (dd, J₁ = 2.3 Hz, J₂ = 8.6 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 4.78(m, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.00 (m, 2H), 2.55-2.52 (m, 2H),1.98-1.96 (m, 1H), 1.83-1.80 (m, 2H), 1.23 (m, 2H) 420.0 (M − 1) 320

12.76 (s, 1H), 11.44 (s, 1H), 7.90 (s, 1H), 7.62 (t, J = 2.2 Hz, 1H),7.28 (t, J = 8.3 Hz, 1H), 7.15 (dd, J₁ = 1.2 Hz, J₂ = 8.1 Hz, 1H), 6.69(dd, J₁ = 2.0 Hz, J₂ = 8.3 Hz, 1H), 3.82 (t, J = 6.1 Hz, 4H), 3.78 (s,3H), 1.77-1.76 (m, 4H), 1.52 (m, 4H) 367.2 321

12.81 (s, 1H), 11.39 (s, 1H), 7.91 (s, 1H), 7.58 (t, J = 2.0 Hz, 1H),7.36 (t, J = 8.1 Hz, 1H), 7.10 (d, J = 9.3 Hz, 1H), 6.71 (dd, J₁ = 2.2Hz, J₂ = 8.1 Hz, 1H), 4.79 (m, 2H), 3.79 (s, 3H), 3.03 (m, 2H), 2.56-2.59 (m, 2H), 2.09-1.98 (m, 1H), 1.84-1.82 (m, 2H), 1.23 (m, 2H) 390.3(M − 1) 322

12.73 (s, 1H), 11.31 (s, 1H), 7.88 (s, 1H), 7.68 (d, J = 8.3 Hz, 2H),7.23 (d, J = 8.3 Hz, 2H), 4.63 (t, J = 5.7 Hz, 1H), 3.81 (t, J = 6.1 Hz,2H), 3.77 (t, J = 5.9 Hz, 2H), 3.60 (q, J = 7.3 Hz, 2H), 2.71 (t, J =6.9 Hz, 2H), 1.78-1.75 (m, 4H), 1.51 (m, 4H) 379.3 (M − 1) 323

12.79 (s, 1H), 11.29 (s, 1H), 7.90 (s, 1H), 7.62 (d, J = 8.3 Hz, 2H),7.25 (d, J = 8.3 Hz, 2H), 4.71 (m, 2H), 4.63 (t, J = 5.1 Hz, 1H), 3.61(q, J = 7.1 Hz, 2H), 3.01 (m, 2H), 2.72 (t, J = 7.1 Hz, 2H), 2.72 (t, J= 7.1 Hz, 2H), 2.55-2.54 (m, 2H), 1.98 (m, 1H), 1.85-1.82 (m, 2H), 1.23(m, 2H) 404.2 (M − 1) 324

12.71 (s, 1H), 11.17 (s, 1H), 7.87 (s, 1H), 7.66 (dd, J₁ = 2.0 Hz, J₂ =6.9 Hz, 2H), 6.96 (dd, J₁ = 2.2 Hz, J₂ = 7.1 Hz, 2H), 4.10-4.08 (m, 2H),3.80 (t, J = 6.1 Hz, 2H), 3.73 (t, J = 5.9 Hz, 2H), 3.67-3.64 (m, 2H),3.31 (s, 3H), 1.75 (m, 4H), 1.50 (m, 4H) 411.3 325

12.77 (s, 1H), 11.15 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 8.8 Hz, 2H),6.99 (d, J = 9.2 Hz, 2H), 4.90-4.60 (m, 2H), 4.10 (t, J = 4.7 Hz, 2H),3.66 (t, J = 4.7 Hz, 2H), 3.02-2.95 (m, 2H), 2.55-2.53 (m, 2H), 2.09-1.97 (m, 1H), 1.84-1.81 (m, 2H), 1.24-1.10 (m, 2H) 436.5 326

12.81 (s, 1H), 11.31 (s, 1H), 7.91 (s, 1H), 7.10 (s, 2H), 4.80 (m, 2H),3.81 (s, 6H), 3.65 (s, 3H), 3.02 (m, 2H), 2.55-2.53 (m, 2H), 1.99 (m,1H), 1.83-1.80 (m, 2H), 1.24 (m, 2H) 452.3 327

12.70 (s, 1H), 11.41 (s, 1H), 7.88 (s, 1H), 7.63 (s, 1H), 7.02 (dd, J₁ =1.9 Hz, J₂ = 8.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.03 (s, 2H), 3.80(t, J = 5.9 Hz, 2H), 3.73 (t, J = 5.7 Hz, 2H), 1.75 (m, 4H), 1.51 (m,4H) 381.3 328

11.20 (s, 1H), 7.89 (s, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.05 (dd, J₁ =2.0 Hz, J₂ = 8.3 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.01 (s, 2H), 4.80(m, 2H), 3.04-2.97 (m, 2H), 2.04-2.01 (m, 1H), 1.89-1.85 (m, 2H), 1.29-1.25 (m, 2H) 406.2 329

— 480.4 330

7.83 (s, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 9.3 Hz, 2H), 5.62(bs, 2H), 4.50 (m, 2H), 3.90-3.86 (m, 1H), 3.49-3.46 (m, 2H), 2.88- 2.83(m, 4H), 2.53 (d, J = 6.4 Hz, 2H), 2.07-2.05 (m, 3H), 1.89-1.86 (m, 2H),1.74-1.68 (m, 2H), 1.22- 1.20 (m, 2H) 569.0 (M − 1) 331

12.74 (s, 1H), 11.33 (s, 1H), 7.89 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H),7.32 (d, J = 8.3 Hz, 2H), 5.15 (t, J = 5.8 Hz, 1H), 4.48 (d, J = 5.9 Hz,2H), 3.81 (t, J = 6.1 Hz, 2H), 3.77 (t, J = 5.9 Hz, 2H), 1.79-1.75 (m,4H), 1.51 (m, 4H) 365.0 (M − 1) 332

12.80 (s, 1H), 11.30 (s, 1H), 7.90 (s, 1H), 7.66 (d, J = 8.3 Hz, 2H),7.35 (d, J = 8.3 Hz, 2H), 5.16 (t, J = 5.6 Hz, 1H), 4.79-4.71 (m, 2H),4.49 (d, J = 5.9 Hz, 2H), 3.01-2.98 (m, 2H), 2.55-2.54 (m, 2H), 2.01-1.95 (m, 1H), 1.85-1.82 (m, 2H), 1.23 (m, 2H) 390.3 (M − 1) 333

12.88 (s, 1H), 11.71 (s, 1H), 8.00- 7.94 (m, 5H), 4.81-4.70 (m, 2H),3.21 (s, 3H), 3.04 (m, 2H), 2.57- 2.55 (m, 2H), 2.01-2.00 (m, 1H), 1.87(m, 2H), 1.25-1.23 (m, 2H) 440.3 334

12.83 (s, 1H), 11.72 (s, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 5.4Hz, 2H), 7.92 (s, 1H), 3.84-3.78 (m, 4H), 3.21 (s, 3H), 1.83-1.76 (m,4H), 1.52 (m, 4H) 415.4 335

15.68 (s, 1H), 12.86 (s, 1H), 11.63 (s, 1H), 8.53 (s, 1H), 7.99-7.94 (m,2H), 7.38 (bs, 1H), 4.80 (m, 2H), 3.07 (m, 2H), 2.58-2.56 (m, 2H),2.02-1.99 (m, 1H), 1.88 (m, 2H), 1.27-1.23 (m, 2H) 401.4 (M − 1) 336

12.77 (s, 1H), 11.29 (s, 1H), 10.80 (s, 1H), 11.60 (s, 1H), 7.91 (s,1H), 7.89 (s, 1H), 7.67 (d, J = 1.0 Hz, 1H), 7.02-7.00 (m, 1H),7.00-6.91 (m, 1H), 4.78-4.71 (m, 2H), 3.03- 2.97 (m, 2H), 2.56-2.54 (m,2H), 1.99-1.93 (m, 1H), 1.86 (m, 2H), 1.24-1.23 (m, 2H) 416.2 (M − 1)337

12.79 (s, 1H), 11.30 (s, 1H), 7.89 (s, 1H), 7.64 (d, J = 8.3 Hz, 2H),7.26 (d, J = 8.3 Hz, 2H), 4.79-4.70 (m, 2H), 4.52 (t, J = 5.9 Hz, 1H),4.40 (t, J = 5.9 Hz, 1H), 3.00 (m, 2H), 2.67 (t, J = 7.6 Hz, 2H), 2.55-2.54 (m, 2H), 2.01-1.91 (m, 3H), 1.85-1.82 (m, 2H), 1.24 (m, 2H) 420.3(M − 1) 338

12.81 (s, 1H), 11.33 (s, 1H), 7.91 (s, 1H), 7.77 (dd, J₁ = 2.0 Hz, J₂ =6.8 Hz, 2H), 7.25-7.21 (m, 2H), 4.80-4.67 (m, 2H), 3.04-2.98 (m, 2H),2.56-2.53 (m, 2H), 2.01-1.96 (m, 1H), 1.86-1.83 (m, 2H), 1.24- 1.21 (m,2H) 426.0 (M − 1) 339

15.67 (s, 1H), 12.81 (s, 1H), 11.68 (s, 1H), 8.63 (s, 1H), 8.00 (m, 1H),7.92 (s, 1H), 7.33 (m, 1H), 3.84 (t, J = 5.9 Hz, 4H), 1.86-1.78 (m, 4H),1.54 (m, 4H) 378.2

The following compounds are anticipated to result in MS having M⁺ valuesnoted in the following Table B.

TABLE B Structure IUPAC Name M⁺

2-(2,6-dimethylpiperidin-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 448.3

2-(1-(4-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid 491.3

6-(4-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane- 1-carboxylic acid 503.3

2-(1-(4-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile 472.3

2-(2,6-dimethylpiperidin-1-yl)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-one 519.3

2-(1-(5-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid 492.3

2-(3,5-dimethylpiperidin-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 448.3

2-(1-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid 491.3

6-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 503.3

2-(1-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile 472.3

2-(3,5-dimethylpiperidin-1-yl)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-one 519.3

2-(1-(5-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid 492.3

2-(2,6-dimethylmorpholino)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 450.1

2-(1-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid 493.2

6-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 505.2

2-(1-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile 474.3

2-(2,6-dimethylmorpholino)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-one 502.3

2-(1-(5-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid 494.2

2-(diisopropylamino)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 436.3

2-(1-(4-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)aceticacid 479.3

6-(4-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane- 1-carboxylic acid 491.3

2-(1-(4-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile 460.3

2-(diisopropylamino)-4-((4-(4-(2-hydroxy-2- methylpropanoyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 507.3

2-(1-(5-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid 480.3

2-(2-methylpiperidin-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-one 434.3

2-(1-(4-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)aceticacid 477.3

6-(4-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 489.3

2-(1-(4-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile 458.3

4-((4-(4-(2-hydroxy-2-methylpropanyl)piperdin-1-yl)phenyl)amino)-2-(2-methylpiperidin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one 505.3

2-(1-(5-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid 478.2

1-(4-((2-(azepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid 463.2

1-(4-((2-(azepan-1-yl)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid 477.3

4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one 501.3

4-((4-((4-(2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one 515.3

2-(1-(4-((2-cycloheptyl-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid 476.3

1-(4-((2-cycloheptyl-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid 462.2

6-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 500.2

2-(1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)aceticacid 488.2

1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid 474.2

1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid 488.2

1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-3-carbonitrile 512.3

2-(1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidin-4-yl)aceticacid 502.2

1-(4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-3-carbonitrile 526.3

1-(4-((2-cycloheptyl-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid 476.3

4-((4-((4-(2H-tetrazol-5-yl)piperidin-1- yl)methyl)phenyl)amino)-2-cycloheptylpyrimido[4,5-d]pyridazin-5(6H)-one 500.3

2-(1-(4-((2-cycloheptyl-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)acetic acid 490.3

4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-2- cycloheptylpyrimido[4,5-d]pyridazin-5(6H)-one514.3

1-(4-((2-(4-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid 474.2

1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-carbonitrile 512.3

1-(4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-carbonitrile 526.3

1-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid 502.2

2-(1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 526.3

2-(1-(4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile 540.3

1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid 489.2

1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid 503.2

2-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-1-yl)acetonitrile 527.3

2-(1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)acetic acid 517.3

2-(4-(4-((4-((4-((2H-tetrazol-5- yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-1-yl)acetonitrile 541.3

6-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 490.2

2-(1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)aceticacid 478.2

1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid 464.2

1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid 452.2

6-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 543.2

2-(1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid 531.2

1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid 517.2

1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid 531.2

3-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-1-yl)-3-oxopropanenitrile 555.3

2-(1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)acetic acid 545.3

4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-2-(4-(2-isocyanoacetyl)piperazin-1-yl)pyrimido[4,5- d]pyridazin-5(6H)-one 569.3

6-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1- carboxylic acid 542.2

2-(1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetic acid 530.2

1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylic acid 516.2

1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylic acid 530.2

3-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-1-yl)-3-oxopropanenitrile 554.3

2-(1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)acetic acid 544.3

4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-2-(1-(2-isocyanoacetyl)piperidin-4-yl)pyrimido[4,5- d]pyridazin-5(6H)-one 568.3

Example 340: Inhibition of Enzymatic Syk Kinase Activity

The objective of this assay was to examine by radiometric method theability of compounds to inhibit Syk kinase enzyme.

A. Background

Spleen tyrosine kinase (Syk) is a cytosolic protein tyrosine kinase thatplays a crucial role in inflammatory and allergic responses. Syktriggers IgE and IgG receptor mediated signaling in mast cells,basophils, and macrophages leading to degranulation and cytokinerelease. Abnormal function of Syk has also been implicated in severalinstances of hematopoietic malignancies.

Syk is capable of phosphorylating substrates such as VAV, LAT, SLP-76,which in turn activate MAPK, PLCγ signaling pathways. Crystallizationstudies of the Syk catalytic domain (360-635) showed more activitycompared to the full length Syk enzyme. This in vitro assay tests theability of syk to phosphorylate a substrate peptide in the presence ofATP. By using a radio-labeled form of ATP, it is possible to measure theamount of phosphorylation of the substrate. The enzyme transfers aradio-labeled phosphate group from γ32 P labeled ATP to pG4T. Brieflythe enzyme was incubated with substrate, radio-labeled & cold ATP andsubstrate in buffer with or without compounds. At the end of thereaction, the reaction mixture was transferred on to a Multiscreenfilter plate and unreacted γ³²P ATP was washed off. The filter plate wasdried and the radioactivity was measured on a scintillation counter toestimate the incorporated radioactivity on the substrate. The percentinhibition of activity of the enzyme was calculated by comparing countsin the presence and absence of compounds.

B. Reagents and Instruments

TABLE 3 Reagent Supplier Poly (Glu, Tyr) sodium salt (4:1) Sigma, Cat#P0275 Syk (356-635 amino acids)-catalytic n/a domain of the full lengthSyk enzyme* Whatman ® P81 Chromatography paper Whatman Cat #3698-915Microtest ™ V-Bottom plates Tarsons, Cat #941396 ATP Sigma, Cat #A7699)[γ-³²P] ATP Jonaki Lab, Hyderabad, Cat #PLC101 Microscint-O ™ reagentPerkin-Elmer, Cat #6013611 DMSO Sigma, Cat #D2650 Top Count ® NXLinstrument Perkin Elmer Optiplate ® 96 well microplate Perkin-Elmer; Cat#6005299 TopSeal-A ® 96 well microplate Perkin Elmer; Cat #6005185 *See,FIG. 2A of Law, “Molecular Cloning of Human Syk”, J. Biol. Chem.,269(16):12310-12319 (1994) which provides the full-length amino acidsequence for human Syk. the fragment utilized included a C′-terminal tagof 4 amino acids and a stretch of 15 amino acids N-terminal to thekinase domain, starting at amino acid 356. See, also, Yagi, “Cloning ofthe cDNA for the Deleted SYK Kinase Homologous to ZAP-70 from HumanBasophilic Leukemia Cell Line (KU812)”, Biochem. Biophys. Res. Commun.,200(1):28-34 (1994). Both of these publications are incorporated byreference herein.

TABLE 4 Tris Buffer composition Reagent Supplier 50 mMtris-hydrochloride (Tris) Sigma, Cat #T5941 10 mM magnesium Sigma, Cat#M9272 chloride (MgCl₂) 2.5 mM Di thiotretol Sigma, Cat #D-0632 (DTT)500 μM sodium Sigma, Cat. #S6508 orthovanadate 500 μM ethylene glycolSigma, Cat #E3889 tetra acetic acid (EGTA) 0.001% Triton ® X-100 LobaChemie, reagent (surfactant CAS #9002-93-1 with molecule formula ofC₁₄H₂₂O(C₂H₄O)n (n = 9-10)C. Protocol

2.5 μL of 10% DMSO or compound in 10% DMSO was added to the wells in a96 well V-bottom plate. Optimized concentration of in-house Syk enzyme(different batches of Syk (356-635) kinase domain) were used atoptimized concentrations) ranging from 0.035 ng to 7.5 ng/reactiondiluted in assay buffer was added to a total volume of 12.5 μL).Compound and protein were incubated for 30 minutes at room temperatureon a plate shaker. Ten μL of a substrate mix containing 100 μM ATP (0.25μL), γ-P³²-ATP (0.1 μL; 10 μCi/μL), pG4T (0.25 μL; 10 mg/mL) and 1×assay buffer (9.4 μL) was added to all the wells. Samples were incubatedat 30° C. for 10 minutes after mixing. The reaction was stopped by theaddition of 8N HCl (13 μL) containing 100 mM ATP. Thirty μL of samplewas transferred to the center of a 2×2 cm² Whatman® P81 chromatographypaper. After allowing the sample to dry for one minute, the assaysquares were washed 3 times for 5 minutes each in ortho-phosphoric acid(0.5%) and once in acetone. Assay squares were dried for 15 minutes in a30° C. oven and transferred to 96 well optiplate. Microscint-O® reagent(100 μL, Perkin Elmer) was added to each well, the plate was sealed withTopseal®-A microplates and incubated for 10 minutes at room temperatureat very low speed on rocker and the plate was read in the Topcount® NXLinstrument.

The following calculations were made:

Fold  induction = radioactivity  counts  (uncorrected  values)  in  positivecontrol/substrate  control.Percent  inhibition  was  calculated  with  the  corrected  values:${\%\mspace{14mu}{inhibition}} = {100 - \frac{\left\{ {{CPM}\mspace{14mu}{for}\mspace{14mu}{reaction}\mspace{14mu}{containing}\mspace{14mu}{compound}*100} \right\}}{\left( {{CPM}\mspace{14mu}{for}\mspace{14mu}{positive}\mspace{14mu}{control}} \right)}}$

The % inhibitions of the compound vs. concentrations of NCE were plottedusing Graphpad® Prism software to calculate the IC₅₀ of the active NCE.

See, Rossi, J. Allergy Clin. Immunol. (2006), 118(3):749-755 and EvaPapp, “Steady State Kinetics of Spleen Tyrosine Kinase Investigated by aReal Time Fluorescence Assay”, Biochemistry (2007) 46:15103-15114, whichare hereby incorporated by reference.

Example 341: Inhibition of Enzymatic JAK2 Kinase Activity

The objective of this assay was to screen compounds in a Time-resolvedfluorescence resonance energy transfer (TR-FRET) Enzymatic assay methodfor their potential to inhibit JAK2 (Janus kinase) activity. Compoundswhich inhibit Syk and JAK2 in these studies may be potentially used intreating inflammation.

A. Background

JAK 2 (Janus kinase 2) is a family of intracellular non-receptortyrosine kinases that transduce cytokine-mediated signals via theJAK-STAT pathway. These kinases have apparent molecular weight of about130 Kda. They were initially named “just another kinase” 1 & 2 (sincethey were just two of a large number of discoveries in a PCR-basedscreen of kinases), but were ultimately published as “Janus kinase”.JAKs possess two near-identical phosphate-transferring domains. Onedomain exhibits the kinase activity while the other negatively regulatesthe kinase activity of the first. They are crucial signal transducersfor a variety of cytokines, growth factors and interferons.

TR-FRET assays are homogeneous proximity assays where Eu-labeledantiphosphotyrosine antibody binds to the phosphorylated substrateslabeled with Ulight fluorescence acceptor. Eu can transfer energy toUlight accepter in the complex and the interaction of two dye-labeledbinding partners is detected by the energy transfer between a donor andan acceptor dye, and the subsequent light emission by the acceptor dye.The intensity of the light emission is proportional to the level ofUlight peptide phosphorylation. See, Rodig, “Disruption of the Jak1 genedemonstrates obligatory and nonredundant roles of the JAKs incytokine-induced biologic responses”, Cell, 93(3):373-83 (1998) andYamaoka, “The Janus kinases (Jaks)”, Genome Biology, 5:253 (2004), whichare incorporated herein by reference.

B. Reagents and Equipment

TABLE 5 Reagent Supplier Ultra light poly GT Perkin Elmer; (4:1)substrate Cat #TRF-0100-D JAK2 Upstate; Cat #14-640 Lance ® Eu-W1024Perkin Elmer; Anti-phosphotyrosine Cat #AD0203 (P-Tyr-100) reagentdimethyl sulfoxide SpectroChem; (DMSO) Cat #0704209 ATP Sigma; Cat#A7699 Wallac ® 1420 multilabel Perkin Elmer, counter victor 3instrument Finland Lumitrac ® 200 384-well Greiner-Bio; plates, mediumbinding, Cat #781075 flat bottom, white color

TABLE 6 Tris Buffer composition Reagent Supplier 50 mM Tris Sigma, Cat#T5941 20 mM MgCl₂ Sigma, Cat #M9272 2 mM DTT Sigma, Cat #D-0632 0.01%Tween ®20 reagent Sigma; Cat #1379 (Polyoxyethylene (20) sorbitanmonolaurate surfactant)C. Protocol

Two μL of 10% DMSO in blank, substrate control and positive controlwells and 2 μL of test compound in test wells was added. Thirteen μL ofassay buffer in blank and substrate control wells and 13 μL of Enzymebuffer mix in positive and test wells was added. The reaction mixturewas incubated for 30 minutes at RT on a plate shaker. Ultra Light-pGTsubstrate (5 μL) [poly Glu-Tyr (4:1) labeled with U Light™ dye, atyrosine kinase substrate] and ATP mix was added to all wells. Thereaction plate was incubated for 60 minutes at RT on a plate shaker. Thereaction was stopped by adding 40 mM EDTA (10 μL) in buffer. Ten μL ofantibody was added to all the wells. The plate was read in a Wallac®1420 Multilabel Counter Victor 3 instrument (Ex: 340 nm Em: 615 & 665nm) The following calculations were made:

F@ 665 Value-Buffer blank

F@ 615 Value-Buffer blank

Ratio: (F@665 Buffer blank/F@615 Buffer blank)*10000

Ratio of F@665/F@615- Substrate Blank

% Activity=(Test Sample/Positive control)*100

% Inhibition=(100-% Activity)

TABLE 7 IC₅₀ ≥100 nM = A; ≤100 nM = B; ≤50 nM = C; ≤10 nM = D Ex. #Structure Syk JAK2 1

C C 2

B A 3

A B 4

B C 5

D C 6

C C 7

C C 8

D D 9

A — 10

C B 11

C B 12

C D 13

C D 14

D — 15

A — 16

A — 17

A — 18

A C 19

C D 20

A — 21

A — 22

B C 23

C B 24

D B 25

C B 26

D B 27

A A 28

A A 29

A — 30

C C 31

C A 32

B A 33

C A 34

C C 35

C C 36

A B 37

D B 38

A — 39

C C 40

C A 41

B A 42

B C 43

C B 44

A A 45

A A 46

B B 47

B B 48

B B 49

B B 50

D A 51

A A 52

D D 53

A B 54

D D 55

A A 56

A C 57

— — 58

A C 59

C A 60

D D 61

A — 62

D D 63

A — 64

A — 65

A — 66

C 67

A 68

B 69

D 70

B A 71

A A 72

C B 73

B — 74

A — 75

B — 76

A — 77

C D 78

B — 79

C D 80

C D 81

C D 82

A — 83

C C 84

C D 85

C D 86

C C 87

C B 88

D D 89

C C 90

B C 91

D C 92

D C 93

C C 94

B — 95

C C 96

D D 97

A — 98

C C 99

D C 100

C C 101

A A 102

C A 103

D D 104

C D 105

D D 106

C C 107

D C 108

D D 109

D D 110

D C 111

C A 112

C D 113

A D 114

D C 115

C C 116

C C 117

C D 118

C D 119

A — 120

C C 121

C C 122

A — 123

D D 124

D D 125

D D 126

B C 127

C C 128

C C 129

D D 130

D D 131

D D 132

C D 133

B C 134

C D 135

D D 136

C C 137

A — 138

A — 139

C D 140

D D 141

C D 142

C D 143

C A 144

B B 145

D D 146

D C 147

D C 148

C C 149

A — 150

C A 151

C C 152

C A 153

C B 154

C C 155

C C 156

C B 157

C C 158

C D 159

C D 160

C C 161

C D 162

D D 163

A — 164

C D 165

B D 166

C C 167

C D 168

C C 169

C C 170

C D 171

C C 172

C D 173

C C 174

C C 175

D D 176

A — 177

A — 178

D D 179

D D 180

D D 181

A A 182

B D 183

D C 184

D D 185

D C 186

D B 187

D C 188

C C 189

D C 190

D D 191

D D 192

D D 193

D D 194

A — 195

D D 196

D D 197

D D 198

D D 199

D D 200

D C 201

D D 202

C D 203

C D 204

A — 205

C C 206

C D 207

D D 208

D D 209

D C 210

C D 211

C C 212

C C 213

D C 214

D D 215

D D 216

D D 217

C C 218

C C 219

D D 220

D D 221

C D 222

B C 223

D D 224

C C 225

A — 226

A — 227

C D 228

C C 229

C D 230

A — 231

C B 232

C D 233

D D 234

C D 235

C C 236

B C 237

C D 238

C D 239

B C 240

C D 241

A — 242

C C 243

C C 244

D D 245

C C 246

D D 247

D D 248

D D 249

C C 250

C D 251

C C 252

C D 253

C D 254

D C 255

C D 256

D C 257

D C 258

B — 259

C C 260

C C 261

D C 262

C D 263

D D 264

D D 265

D D 266

D C 267

D D 268

D C 269

C C 270

C C 271

D C 272

C D 273

D D 274

D D 275

D D 276

D C 277

D C 278

C C 279

A — 280

C D 281

C D 282

C D 283

D D 284

D D 285

C C 286

C C 287

C C 288

C C 289

C D 290

C C 291

C C 292

D D 293

B C 294

C C 295

C C 296

B — 297

D C 298

A — 299

C C 300

A — 301

A — 302

A — 303

A — 304

D D 305

D C 306

D D 307

D D 308

C D 309

C C 310

A — 311

A — 312

A — 313

A — 314

C D 315

C C 316

C D 317

A — 318

A — 319

A — 320

A — 321

A — 322

C D 323

C C 324

C C 325

C C 326

A — 327

A — 328

A — 329

D D 330

A — 331

C A 332

B — 333

A — 334

C D 335

C C 336

C C 337

C C 338

B A 339

D C

Example 342: Degranulation Assay

The objective of this assay was to examine by Fluorescence method theeffect of compounds on β-hexosaminidase release during immune complexmediated degranulation in RBL2H₃ cells.

A. Introduction

Auto-antibodies and their immune complexes (ICs) reacting with selfantigens through immunoglobulin receptors have been implicated widely ininflammation and chronic inflammatory disease such as rheumatoidarthritis. Activation of the high affinity receptor for immunoglobulin E(IgE), FcεRI, which is expressed on the surface of mast cells andbasophils, plays a central role in the initiation of these allergicresponses. Following aggregation of the receptor by ICs, the mast cellrelease a variety of potent biologically active molecules, includingcytokines, lipid-derived mediators, amines, protease, and proteoglycans.Anti-DNP (anti-dinitrophenyl) IgE treated RBL2H₃ cells on stimulationwith DNP-BSA leads to FcεR1 cross linking which mediates release ofvarious pro-inflammatory molecules including β-hexosaminidase.

Compounds were tested for their ability to inhibit the ability of thisimmune complex to mediate β-hexosaminidase release, in an enzyme assaywith p-nitrophenyl-β-D-glucosaminide as substrate. The fluorescence ofthe product 4-methylumbellifernone was monitored (Excitation 355 nm;Emission 460 nm).

B. Reagents and Instruments

TABLE 8 Reagent Supplier Rat Basophilic ATCC, Cat # Leukemia cell lineCRL-2256 (RBL2H3 cell line) Minimum Essential GIBCO, Medium (MEM) Cat #12571 Fetal Bovine Serum (FBS) Hyclone, Cat # SH30071.03 Pencilin (10000unit/mL)- GIBCO, Cat #15140-122 Streptomycin (10,000 μg/mL) (Penstrep ®reagent) MEM Sodium Pyruvate GIBCO, Cat # 11360 solution, 100 mMNonessential amino GIBCO, Cat # 11140 acid (NEAA) 0.1% Trypsin and 0.1%SAFC Biosciences, EDTA (0.1% TE) Cat # 59417C 96-well flat bottom plateFalcon, Cat # 3072 100% Dimethyl Sulfoxide SIGMA-D-5879 (DMSO; Vehicle)SPE-7 Anti-Dinitrophenyl (DNP) Monoclonal Rat IgE, Clone SPE-7 (Sigma,Cat #D8406) 2,4-Dinitrophenylated Albumin Invitrogen, Cat from bovineserum (DNP-BSA) #A23018 4-Methylumbelliferyl N-acetyl-β- Sigma, Cat#2133 D-glucosaminide dihydrate (β-NAG) 0.1M Sodium Carbonate/SodiumNa₂CO₃: Sigma, Cat # S5761 Bicarbonate, pH 10.08 NaHCO₃: Sdfine-Chemicals (Stop Solution) Ltd, Cat # 40121 Phosphate Buffer Saline(PBS) Himedia, Cat # TS1006 96 well View Plate PerkinElmer, Part#6005182 24 well plate Falcon, Cat # 3047 Victor ™ X5 MultiPerkin-Elmer, label plate Fluorescence Product #2030-0050 Reader

TABLE 9 Pipes Buffer composition Reagent Supplier 25 mMpiperazine-1,4-bis Sigma Cat # P1851 (2-ethanesulfonic acid) (Pipes) 125mM sodium chloride (NaCl) Qualigens Cat # 15918 2.7 mM potassiumchloride (KCl) Sigma Cat # P9541 5.6 mM anhydrous D-glucose QualigensCat # 24415 1 mM calcium chloride (CaCl₂) Qualigens Cat # 22205 0.1%bovine serum albumin (BSA) Sigma Cat # A7030C. Protocols

(i) Protocol A: 24 well format

RBL2H₃ cells were maintained in MEM complete media containing 10% FBS at70%-80% confluence in a mammalian cell culture CO₂ incubator with 5% CO₂at 37° C. 2×10⁵ cells/well were plated in 1 mL of complete media andincubated for 5 hours for cell attachment. Complete media was replacedwith 1 mL of serum free MEM media containing 1.2 μg/mL of anti-DNP ratIgE as sensitizing agent and further incubated overnight with 5% CO₂ at37° C. The following day, cells were washed with serum free media andfurther treated with various concentrations of test compounds (in 0.1%DMSO) for 45 minutes at 37° C. and 5% CO₂. Cells were further stimulatedwith 5 μg/mL of DNP-BSA for 60 minutes. Plates were centrifuged for 5minutes at 1000 rpm and 25 μL of culture supernatant was transferredfrom each assay well into a 96 well black coated plate. 25 μL β-NAGsubstrate was added to this mixture and incubated at room temperaturefor 30 minutes. The reaction was terminated with 100 μL of stop solutionand fluorescence was monitored. (Excitation 355 nm; Emission 460 nm)See, Sanderson, (2010), Cellular Immunology, 262(1): 28-34 andSilverman, (2006) MCB, 26(5):1826-1838, which are incorporated herein byreference.

The % release of β-Hexosaminidase for the test compound was calculatedusing the following formula:

${\%\mspace{14mu}\beta\text{-}{Hexosaminidase}\mspace{14mu}{release}} = {\left( \frac{{{test}\mspace{14mu}{compound}} - {{DMSO}\mspace{14mu}{control}}}{{{IgE}\mspace{14mu}{control}} - {{DMSO}\mspace{14mu}{Control}}} \right) \times 100}$

(ii) Protocol B: 96 well format

RBL2H₃ cells were maintained in MEM complete media containing 10% FBS at70-80% confluence in a mammalian cell culture CO₂ incubator with 5% CO₂at 37° C. 5×10⁴ cells/well were plated in 200 μL of complete mediacontaining 0.3 μg/mL of anti-DNP rat IgE as sensitizing agent for 24hours at 37° C. & 5% CO₂. The following day, cells were washed twicewith PIPES buffer for 10 minutes at 37° C. and replenished with serumfree MEM media. Cells were treated with various concentrations of testcompounds (in 0.5% DMSO) for 15 minutes at 37° C. and 5% CO₂. The cellswere further stimulated with 0.1 μg/mL of DNP-BSA for 45 minutes. Theplates were spun for 5 minutes at 2000 rpm and 25 μL of culturesupernatant was then transferred from each assay well into a 96 wellblack coated plate. Fifth μL β-NAG substrate was added and incubated atRT for 30 minutes. After incubation with substrate, 150 μL of stopsolution was added and fluorescence was monitored. (Excitation 355 nm;Emission 460 nm). See, Yamamoto, JPET, 306(3):1174-1181 (2003) andTaylor, MCB, 15(8): 4149-4157 (1995), which are herein incorporated byreference.

Release of β-hexosaminidase during the degranulation process by immunecomplex mediated FcεRI stimulation is through the SYK pathway. The %inhibition of β-hexosaminidase release by Syk inhibitor givesinformation with regard to its Syk inhibition potency. Thus compoundshaving lower EC₅₀ values are more potent in inhibiting immune complexmediated Syk signaling during degranulation process.

TABLE 10 Degranulation Degranu- % lation inhibition EC₅₀ Assay Ex. # at1 μM (nM) Protocol 1 85 — A 5 100 39 A 6 50 — A 7 92 86 A 8 98 — A 10100 — A 11 100 — A 13 100 47 A 19 100 19 A 24 83 — B 25 79 — A 26 67 — B30 99 — B 33 58 — B 34 80 378 B 35 19 — B 39 100 — B 43 13 — B 47 100132 B 48 100 — B 50 49 — B 52 100 1 B 54 100 13 B 60 100 18 B 62 100 49B 66 75 352 B 68 100 1.2 B 69 100 31 B 71 65 1017 B 88 100 76 B 89 100 —B 91 100 154 B 92 100 111 B 93 49 — B 95 35 — B 96 85 280 B 98 62 593 B99 94 44 B 103 87 32 B 104 100 110 B 107 91 94 B 108 98 68 B 116 65 273B 117 89 95 B 118 87 153 B 121 98 156 B 123 90 116 B 125 38 238 B 131 9835 B 132 99 24 B 133 98 25 B 145 52 98 B 146 66 26 B 147 49 152 B 151 —24 B 153 47 324 B 154 23 2320 B 155 — 27 B 157 70 42 B 158 53 162 B 15968 56 B 161 74 39 B 162 27 281 B 164 — 55 B 169 17 230 B 170 39 107 B172 50 101 B 173 66 29 B 174 99 15 B 175 98 6 B 178 73 39 B 179 45 9 B180 70 3 B 183 41 83 B 184 65 33 B 185 83 29 B 186 93 10 B 187 100 12 B189 98 14 B 190 83 21 B 191 92 21 B 192 82 27 B 193 93 17 B 200 71 66 B201 88 31 B 208 21 14 B 209 81 29 B 210 79 22 B 211 53 49 B 212 71 28 B213 78 33 B 214 78 19 B 215 96 12 B 216 92 21 B 218 33 123 B 219 45 96 B231 0 367 B 232 0 619 B 233 20 174 B 244 23 306 B 248 99 19 B 254 241200 B 256 73 33 B 261 87 39 B 264 75 54 B 265 79 30 B 266 99 10 B 26790 21 B 268 93 20 B 273 91 21 B 274 59 81 B 275 73 15 B 276 91 24 B 27774 42 B 283 71 39 B 284 92 21 B 287 97 20 B 290 100 20 B 292 65 83 B 29799 18 B 304 70 55 B 305 17 834 B 306 100 15 B 307 14 312 B 329 69 62 B339 83 31 B

Example 343: In Vivo Assay—Chronic Study

A. Introduction

Collagen Induced Arthritis (CIA) is a well characterized model of humanrheumatoid arthritis (RA) that can be induced in susceptible animalsfollowing immunization with type II collagen (cII) in Freund's adjuvant.CIA exhibits several features of human RA such as severeswelling/inflammation of joints, synovial hyperplasia, cartilagedestruction and bone erosion. Pathophysiology of CIA consists of T cellcomponent, as evidenced by increased infiltration of T-cells in jointsynovium and also, by attenuation of CIA in T-cell deficient mice. CIAdevelopment involves B cell component too, as is evidenced bycirculating cII antibody in disease animals and also, failure to developthe disease in xid mice/B cell deficient mice/CXCR5 null mice. Recently,a significant role of macrophages has also been suggested in thepathogenesis of CIA as well as human RA. See, Pine, “Inflammation andbone erosion are suppressed in models of rheumatoid arthritis followingtreatment with a novel Syk inhibitor”, Clin. Immunol., 2007,124(3):244-57; Xiong cha, “Suppression of the onset and progression ofcollagen-induced arthritis in rats by QFGJS, a preparation from ananti-arthritic Chinese herbal formula”, J. Ethnopharmacology (2007)110:39-48; and Stolina, “The evolving systemic and local biomarkermilieu at different stages of disease progression in rat collageninduced arthritis”, Biomarkers (2008) 13(7-8):692-712, which are hereinincorporated by reference.

B. Method

(i) Induction of CIA:

Female Lewis rats (8 per group, 6-8 weeks old) were immunized on day 1with type II collagen (Immunization grade Bovine type II; Chondrex; Cat#20021) emulsified with Complete Freund's Adjuvant (Sigma; Cat # F5881)at a final concentration of 1.2 mg/mL). For the initial immunization,the animals were injected at the base of the tail with 300 μg of the cII(0.25 mL/rat). A booster injection of the same type II collagenemulsified with Incomplete Freund's Adjuvant (Sigma, Cat #F5506) (0.25mL/rat) was given to the animals on day 8 at the base of the tail (100μg). The final cII concentration in the booster was 0.4 μg/mL.

(ii) Dosage regimen

Animals with an arthritic score of ≥1 were grouped and dosing with testcompound (30 mg/kg bid) or methotrexate (0.5 mg/kg) started betweenabout day 12 to day 14, with daily dosing of their respective compoundscontinuing for 10 days.

(iii) Measurements:

Edema: Paw volumes are measured by Plethysmometry for the animals beforeinduction of CIA (Basal readings) and on Day 1, 3, 6 and 9 of dosingperiod. Both hind paw volumes were measured and edema was calculated bysubtracting from the basal mean.

Arthritic score: Animals were scored for the symptoms of arthritis everyday starting from Day of onset of disease till the end of the study.Both the hind paws were scored and the total scores were averaged andcompared with control. The scoring pattern was as follows:

TABLE 11 Severity score Gross pathology 0 No evidence of erythema orswelling 1 Erythema and mild swelling confined to mid foot or anklejoint 2 Erythema and moderate swelling extending from ankle to mid foot3 Erythema and moderate swelling extending from ankle to metatarsaljoints 4 Erythema and severe swelling ankle, foot and digitsC. Results

(i) Calculations

The percent inhibition of Edema was calculated with respect to controlby the formula:

${\%\mspace{14mu}{inhibition}\mspace{14mu}{of}\mspace{14mu}{Edema}} = {\left( {1 - \begin{Bmatrix}\frac{{Mean}\mspace{14mu}{Edema}\mspace{14mu}{in}\mspace{14mu}{treated}\mspace{14mu}{animals}\mspace{14mu}{on}\mspace{14mu}{day}\mspace{14mu}{‘n’}}{\left( {{Mean}\mspace{14mu}{Edema}\mspace{14mu}{in}\mspace{14mu}{treated}\mspace{14mu}{animals}\mspace{14mu}{on}\mspace{14mu}{day}\mspace{14mu}{‘0’}} \right)} \\\left( {{Mean}\mspace{14mu}{Edema}\mspace{14mu}{in}\mspace{14mu}{control}\mspace{14mu}{animals}\mspace{14mu}{on}\mspace{14mu}{day}\mspace{14mu}{‘n’}} \right) \\\left( {{Mean}\mspace{14mu}{Edema}\mspace{14mu}{in}\mspace{14mu}{control}\mspace{14mu}{animals}\mspace{14mu}{on}\mspace{14mu}{day}\mspace{14mu}{‘0’}} \right)\end{Bmatrix}} \right) \times 100}$

The percent inhibition of Arthritic score was calculated with respect tocontrol by the formula:

${\%\mspace{14mu}{inhibition}\mspace{14mu}{of}\mspace{14mu}{Score}} = {\left( {1 - \begin{Bmatrix}\frac{{Mean}\mspace{14mu}{score}\mspace{14mu}{in}\mspace{14mu}{treated}\mspace{14mu}{animals}\mspace{14mu}{on}\mspace{14mu}{day}\mspace{14mu}{‘n’}}{\left( {{Mean}\mspace{14mu}{score}\mspace{14mu}{in}\mspace{14mu}{treated}\mspace{14mu}{animals}\mspace{14mu}{on}\mspace{14mu}{day}\mspace{14mu}{‘0’}} \right)} \\\left( {{Mean}\mspace{14mu}{score}\mspace{14mu}{in}\mspace{14mu}{control}\mspace{14mu}{animals}\mspace{14mu}{on}\mspace{14mu}{day}\mspace{14mu}{‘n’}} \right) \\\left( {{Mean}\mspace{14mu}{score}\mspace{14mu}{in}\mspace{14mu}{control}\mspace{14mu}{animals}\mspace{14mu}{on}\mspace{14mu}{day}\mspace{14mu}{‘0’}} \right)\end{Bmatrix}} \right) \times 100}$

(ii) Statistical Analysis

Means of different groups were compared with control using one way ANOVAfollowed by Dunnett's test. Significance is represented as follows.

This example illustrates that the compounds may be utilized for treatinginflammation. See FIGS. 1-2.

TABLE 12 Percent Percent inhibition inhibition of of Edema Arthriticscore (Day 9 (Day 10 Group of dosing) of dosing) Control 0  0   Example19 (2 × 30 mg/Kg) 5** 20*  Methotrexate (0.5 mg/Kg) 6  15   Example 62(2 × 30 mg/Kg) 69*** 81*** Example 108 (2 × 30 mg/Kg) 42*** 53***Example 189 (2 × 30 mg/Kg) 90*** 94*** Example 191 (2 × 30 mg/Kg) 90***100*** *p < 0.05, **p < 0.01, ***p < 0.001

Example 344: In Vivo Assay—Acute Study

A. Introduction

Arthus reaction is a type of local type III hypersensitivity reaction.Type III hypersensitivity reactions are immune complex-mediated, andinvolve the deposition of antigen/antibody complexes mainly in thevascular walls, serosa (pleura, pericardium, synovium), and glomeruli.This involves formation of antigen/antibody complexes after theintradermal injection of an antibody. If the animal was previouslyinjected with antigen and dye (has circulating antigen), an Arthusreaction occurs. This manifests as local vasculitis due to deposition ofimmune complexes in dermal blood vessels. Activation of complement andrecruitment of PMNs ensue, resulting in an inflammatory response andextravasation of dye to the skin. Compounds which can inhibit thiscomplex process can have therapeutic implications in wide range ofinflammatory and auto-immune disorders. See, Pine, “Inflammation andbone erosion are suppressed in models of rheumatoid arthritis followingtreatment with a novel Syk inhibitor”; Clin. Immunol. (2007) 124 (3):244-57; and Sylvia, “R-406, an Orally Available Spleen Tyrosine KinaseInhibitor Blocks Fc Receptor Signaling and Reduces ImmuneComplex-Mediated Inflammation”, JPET 319:998-1008, 2006, which areherein incorporated by reference.

B. Immunization and Challenge

Female c57BL/6 mice were given an antigen injection in which the antigenwas 0.1% Ovalbumin (OVA) in PBS containing 1% Evans blue (EB) at theconcentration of 10 mL/kg intravenously under Isoflurane anesthesia [2.5mg/mouse with a body weight of 25 g]. Ten minutes after antigeninjection; the animals were injected with the rabbit anti-OVA IgG (50 μgin 25 L/site) (Polysciences; Cat #23744) intradermally on the shavedback at two top locations. Animals were also injected with phosphatebuffered saline (PBS, 25 μL) intradermally on the back at two bottom andopposite locations to serve as negative control. The mice wereeuthanized by cervical dislocation 4 hours after antigen (Ovalbumin)challenge. Skin tissue was assessed for edema by tracing the edema areaon to a transparent plastic sheet. Punch biopsies of the injection siteswere collected.

C. Measurements

(i) Area of Extravasation

Edema area was measured manually by scale. Two diameters were taken andaveraged for each animal.

(ii) Extent of Dye Extravasation

Punch biopsies of the injection sites (using 10 mm skin biopsy punches)were incubated in 2 mL of sodium sulfate: acetone mixture (0.6+1.4 mL)at room temperature for 16-18 hours. The supernatants were removed fromdigested tissues by centrifuging at 4000 rpm for 10 minutes, filteredand were read spectrophotometrically at 610 nm.

D. Data Analysis

The percent inhibition of dye leakage was calculated with respect tocontrol by the formula:

${{Percent}\mspace{14mu}{inhibition}\mspace{14mu}{of}\mspace{14mu}{OD}} = {\left\{ {1 - \left( \frac{{Mean}\mspace{14mu}{OD}\mspace{14mu}{in}\mspace{14mu}{treated}\mspace{14mu}{animals}}{{Mean}\mspace{14mu}{OD}\mspace{14mu}{in}\mspace{14mu}{control}\mspace{14mu}{animals}} \right)} \right\} \times 100}$

The percent inhibition of edema area was calculated with respect tocontrol by the formula:

${{Percent}\mspace{14mu}{inhibition}\mspace{14mu}{of}\mspace{14mu}{edema}\mspace{14mu}{area}} = {\left\{ {1 - \left( \frac{{Mean}\mspace{14mu}{edema}\mspace{14mu}{area}\mspace{14mu}{in}\mspace{14mu}{treated}\mspace{14mu}{animals}}{{Mean}\mspace{14mu}{edema}\mspace{14mu}{area}\mspace{14mu}{in}\mspace{14mu}{control}\mspace{14mu}{animals}} \right)} \right\} \times 100}$E. Statistical Analysis:

Means of different groups were compared with control using One way ANOVAfollowed by Dunnett's test. Significance was represented as follows.

This example illustrates that the compounds described herein may beutilized in treating inflammation.

TABLE 13 Efficacy of NCEs in Arthus reaction model in mice Edema area ODDose % % Example (mg/Kg) Inhibition Inhibition 7 30 74*** 65*** 10 53***36   10 30   NE 13 10 53*** 27   30 40**  30   19 3 48*** 53*** 30 60***60*** 7 3 41*** 40*** 10 45*** 41*** 30 68*** 67*** *p < 0.05, **p <0.01, ***p < 0.001

All publications cited in this specification are incorporated herein byreference. While the invention has been described with reference toparticular embodiments, it will be appreciated that modifications can bemade without departing from the spirit of the invention. Suchmodifications are intended to fall within the scope of the appendedclaims.

What is claimed is:
 1. A pharmaceutical composition comprising acompound of Formula (I):

wherein: R¹ is NR⁴R⁵, optionally substituted C₁ to C₆ alkoxy, optionallysubstituted C₆ to C₁₄ aryl, optionally substituted heteroaryl,optionally substituted 3-10 membered monocyclic or bicyclic cycloalkyl,or optionally substituted 3-10 membered monocyclic or bicyclicheterocyclyl, wherein: (i) 3-4 membered cycloalkyl and heterocyclyl aresaturated; (ii) hydrogen atoms on the same carbon atom of saidcycloalkyl or heterocyclyl are optionally replaced with an optionallysubstituted 3-6 membered cycloalkyl or heterocyclyl to form aspirocycloalkyl or spiroheterocyclyl; and (iii) hydrogen atoms on thesame atom of said cycloalkyl or heterocyclyl are optionally replacedwith 0 to form an oxo substituent; R² is optionally substituted phenyl,—O—(C₁ to C₆ alkyl)-optionally substituted phenyl, or optionallysubstituted 5-6 membered heteroaryl, with the proviso that when R² is4-pyridyl, the 4-pyridyl lacks a carbonyl substituent at the 2^(nd)position; R⁴ and R⁵ are: (a) independently selected from the groupconsisting of H, C₁ to C₆ alkyl, C₁ to C₆ hydroxyalkyl, C₃ to C₈cycloalkyl, and —(C₁ to C₆ alkyl)N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl); (b)joined to form an optionally substituted 3-8 membered heterocyclyl,wherein; (bi) hydrogen atoms on the same carbon atom of saidheterocyclyl are optionally replaced with an optionally substituted 3-6membered cycloalkyl or heterocyclyl to form a spirocycloalkyl orspiroheterocyclyl; and (bii) hydrogen atoms on the same atom of saidheterocyclyl (b), cycloalkyl (bi), or heterocyclyl (bi), are optionallyreplaced with 0 to form an oxo substituent; or a pharmaceuticallyacceptable salt or ester thereof, a pharmaceutically acceptable carrier,and one or more excipients.
 2. The pharmaceutical composition accordingto claim 1, wherein R² is phenyl substituted with C(O)NR⁴R⁵.
 3. Thepharmaceutical composition according to claim 1, where R² is phenylsubstituted with NR⁴R⁵.
 4. The pharmaceutical composition according toclaim 1, where R² is phenyl substituted with (C₁ to C₆ alkyl)NR⁴R⁵. 5.The pharmaceutical composition according to claim 1, wherein R⁴ and R⁵are joined to form an optionally substituted piperidine or diazepane. 6.The pharmaceutical composition according to claim 1, wherein R⁴ and R⁵are (C₁ to C₆ hydroxyalkyl).
 7. The pharmaceutical composition accordingto claim 1, wherein R⁴ and R⁵ are joined to form an optionallysubstituted 6-membered ring.
 8. The pharmaceutical composition accordingto claim 1, wherein R² is a heteroaryl substituted with (C₁ to C₆alkyl)NR⁴R⁵.
 9. The pharmaceutical composition according to claim 1,wherein R² is a heteroaryl substituted with NR⁴R⁵.
 10. Thepharmaceutical composition according to claim 1, wherein R² is phenylsubstituted with one or more C₁ to C₆ alkoxy, (C₁ to C₆ alkyl)halogen,C₁ to C₆ trifluoroalkoxy, (C₁ to C₆ alkyl)C(O(OH, halogen, optionallysubstituted C₃ to C₈ cycloalkyl, optionally substituted heterocyclyl,optionally substituted heteroaryl, —O—(C₁ to C₆ alkyl)C(O)OH, —O—(C₁ toC₆ alkyl)-NR⁴R⁵, —O-(optionally substituted heterocycle), —O(C₁ to C₆alkyl)-N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl), —O—(C₁ to C₆ alkyl)NH₂, C₁ toC₆ hydroxyalkyl, —O—(C₁ to C₆ hydroxyalkyl), O—(C₁ to C₆ alkyl)-C(O)OH,—C₁ to C₆ alkoxy-C₁ to C₆ alkoxy, O-(heterocycle)-(C₁ to C₆hydroxyalkyl), SO₂—(C₁ to C₆ alkyl), or —(C₁ to C₆ alkyl)-(C₁ to C₆alkoxy)-halogen.
 11. The pharmaceutical composition according to claim1, wherein R² is —O—(C₁ to C₆ alkyl)NR⁴R⁵.
 12. The pharmaceuticalcomposition according to claim 1, wherein R² is aryl substituted with—O—(C₁ to C₆ alkyl)-heterocycle.
 13. The pharmaceutical compositionaccording to claim 1, wherein R¹ is N(C₁ to C₆ alkyl)(C₁ to C₆ alkyl) orC₁ to C₆ alkoxy.
 14. The pharmaceutical composition according to claim1, wherein R¹ is optionally substituted phenyl.
 15. The pharmaceuticalcomposition according to claim 1, wherein R¹ is optionally substituted5-9 membered saturated heterocyclyl.
 16. The pharmaceutical compositionaccording to claim 1, wherein R¹ is a heterocyclyl of the structure:

wherein: f, g, h, j, and m are, independently, absent, (CH₂), CH(R³), Z,or C═O; R³ is H, C(O)OH, or C(O)O(C) to C₆ alkyl); R⁴⁵, R⁴⁶, R⁴⁷, andR⁴⁸ are, independently, H or C₁ to C₆ alkyl; and Z is O, S, SO, SO₂, orNH.
 17. The pharmaceutical composition according to claim 1, wherein R¹is a heteroaryl.
 18. The pharmaceutical composition according to claim1, wherein R¹ is a monocyclic C₃ to C₈ cycloalkyl.
 19. Thepharmaceutical composition according to claim 1, wherein R¹ ispiperidine substituted with C(O)(C₁ to C₆ alkyl)CN.
 20. Thepharmaceutical composition according claim 1, wherein the compound is asalt of an acid.
 21. The pharmaceutical composition according to claim20, wherein said acid is selected from the group consisting of acetic,propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic,mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric,nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic,toluenesulfonic, trifluoroacetic, and camphorsulfonic.
 22. Thepharmaceutical composition according to claim 1, wherein the compoundis:4-(4-morpholinophenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;methyl4-(5-oxo-4-(4-(piperazin-1-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)benzoatehydrochloride;2-morpholino-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;4-(4-(morpholinomethyl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;4-(4-(4-ethylpiperazin-1-yl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;4-(4-((4-ethylpiperazin-1-yl)methyl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;2-phenyl-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;2-phenyl-4-(4-(piperazin-1-yl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-one;4-(4-(morpholine-4-carbonyl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;4-(4-(bis(2-hydroxyethyl)amino)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;4-(4-(4-(2-aminoacetyl)piperazin-1-yl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;2-(4-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)piperazin-1-yl)aceticacid;1-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)piperidine-4-carboxylicacid;4-(4-(4-(2-aminoacetyl)piperazin-1-yl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;N-(2-(dimethylamino)ethyl)-N-methyl-4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)benzamide;4-(4-(2-oxo-1,7-diazaspiro[3.5]nonan-7-yl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;4-(4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;4-(4-morpholinophenylamino)-2-(6-azaspiro[2.5]octan-6-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;6-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid; ethyl6-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)-6-azaspiro[2.5]octane-1-carboxylate;6-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)benzyl)-6-azaspiro[2.5]octane-1-carboxylicacid; sodium6-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)-6-azaspiro[2.5]octane-1-carboxylate;4-(4-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;4-(4-(piperazin-1-ylmethyl)phenylamino)-2-(thiophen-3-yl)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;6-(5-oxo-4-(4-(piperazin-1-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)-6-azaspiro[2.5]octane-1-carboxylicacid hydrochloride;4-(4-(4-ethylpiperazin-1-yl)phenylamino)-2-morpholinopyrimido[4,5-d]pyridazin-5(6H)-one;4-(5-oxo-4-(4-(piperazin-1-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)benzoicacid hydrochloride;4-(4-(4-ethylpiperazin-1-yl)phenylamino)-2-(4-(trifluoromethoxy)phenyl)pyrimido[4,5-d]pyridazin-5(6H)-one;methyl4-(4-(4-morpholinophenylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)benzoate;4-(4-(piperazin-1-ylmethyl)phenylamino)-2-(piperidin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;2-(3-methoxyphenyl)-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;2-(piperazin-1-yl)-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-onedihydrochloride;2-(benzo[d][1,3]dioxol-5-yl)-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;2-(1-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)piperidin-4-yl)aceticacid;1-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)benzyl)piperidine-4-carboxylicacid;2-(2-methoxyphenyl)-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;4-(4-(4-ethylpiperazin-1-yl)phenylamino)-2-(thiophen-3-yl)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;9-(5-oxo-4-(4-(piperazin-1-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)-3,9-diazaspiro[5.5]undecane-2,4-dionehydrochloride;6-(4-(5-oxo-2-(thiophen-3-yl)-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(4-chlorophenyl)-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;2-(4-methoxyphenyl)-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;6-(4-((2-morpholino-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(1-(5-oxo-4-((4-(piperazin-1-ylmethyl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)aceticacid hydrochloride;2-(1-oxidothiomorpholino)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;2-(4-methylpiperazin-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;6-(4-((2-(4-methoxyphenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;6-(4-((2-(3-methoxyphenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;4-((4-(piperazin-1-ylmethyl)phenyl)amino)-2-(pyrrolidin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;2-(dimethylamino)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;2-ethoxy-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;1-(5-oxo-4-((4-(piperazin-1-ylmethyl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-carboxylicacid hydrochloride;2-(azepan-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;6-(4-((2-(2-methoxyphenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(diisopropylamino)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;2-(4-(morpholinomethyl)phenyl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;1-(5-oxo-4-((4-(piperazin-1-ylmethyl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-carbonitrilehydrochloride;2-(4-ethylpiperazin-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;4-((1-(2-morpholinoethyl)-1H-pyrazol-4-yl)amino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;2-(1,4-diazepan-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-onedihydrochloride;2-(azepan-1-yl)-4-((4-morpholinophenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-methoxy-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;6-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-phenyl-4-((1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;4-((1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;4-((1-(2-(4-ethylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;6-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(azepan-1-yl)-4-((3,4,5-trimethoxyphenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(morpholine-4-carbonyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;2-(1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;2-(1-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;6-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid hydrochloride;6-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;6-(4-((2-(4-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(1-(4-((2-(4-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;1-(4-((2-(4-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylicacid;2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)aceticacid;1-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylicacid;6-(4-((2-cyclohexyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;6-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(1-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;4-((4-((4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)methyl)phenyl)amino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-((4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)methyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(4-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-1-yl)aceticacid;2-(4-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)cyclohexyl)aceticacid;2-(1-(4-((2-(azocan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;2-(azepan-1-yl)-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;2-(1-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;2-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)cyclohexyl)aceticacid;4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)butanoicacid;2-(azepan-1-yl)-4-((4-(2-morpholinoethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;4-((4-(2-morpholinoethoxy)phenyl)amino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(2-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)ethyl)piperidin-4-yl)aceticacid;2-(1-(5-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetonitrile;1-(2-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)ethyl)piperidine-4-carboxylicacid;2-(1-(5-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetamide;2-(1-(4-((2-(4-(2-cyanopropan-2-yl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;2-(1-(5-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(5-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetamide;2-(1-(5-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(piperazine-1-carbonyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetamide;2-(4-(2-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)ethyl)piperazin-1-yl)aceticacid;2-(azepan-1-yl)-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(5-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)aceticacid;2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)-N-(2-hydroxyethyl)acetamide;2-(azepan-1-yl)-4-((4-(((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)-2-methylpropanenitrile;2-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)-2-methylpropanamide;2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;2-(1-(5-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(2-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(5-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)aceticacid;2-(1-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)-N,N-bis(2-hydroxyethyl)acetamide;2-methyl-2-(1-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)propanenitrile;2-(4-(2-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)ethyl)piperazin-1-yl)-2-methylpropanenitrile;2-(1-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;4-((4-(((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methoxy)phenyl)amino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;2-((1S,4S)-4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)cyclohexyl)aceticacid;(2R,5S)-5-((4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)methyl)-1,4-dioxane-2-carboxylicacid;2-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)aceticacid;2-(1-(3-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)propyl)piperidin-4-yl)aceticacid;6-(4-((2-(cyclohexylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)spiro[2.5]octane-1-carboxylicacid;6-(4-((5-oxo-2-(piperidin-1-yl)-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)spiro[2.5]octane-1-carboxylicacid;2-((1R,4R)-4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)cyclohexyl)aceticacid;3-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)propanoicacid;2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)cyclopropanecarboxylicacid;3-(1-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)propanoicacid;6-(4-((2-(4-fluorophenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;6-(5-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)-6-azaspiro[2.5]octane-1-carboxylicacid;6-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)-2-fluorophenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(azepan-1-yl)-4-((4-(3-(piperazin-1-yl)propoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;6-(5-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)-6-azaspiro[2.5]octane-1-carboxylicacid;6-(4-((5-oxo-2-(pyridin-4-yl)-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(azepan-1-yl)-4-((4-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)-2-methylpropanoicacid;6-(4-((2-(azocan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)-2-methylpropanoicacid;2-methyl-2-(1-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)propanoicacid;2-(2,6-dimethylpiperidin-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;6-(4-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(1-(4-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;2-(2,6-dimethylpiperidin-1-yl)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(5-((2-(2,6-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)aceticacid;2-(3,5-dimethylpiperidin-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;6-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(1-(4-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;2-(3,5-dimethylpiperidin-1-yl)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(5-((2-(3,5-dimethylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)aceticacid;2-(2,6-dimethylmorpholino)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;6-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(1-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;2-(2,6-dimethylmorpholino)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(5-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)aceticacid;2-(diisopropylamino)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;6-(4-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(1-(4-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;2-(diisopropylamino)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(5-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)aceticacid;2-(2-methylpiperidin-1-yl)-4-((4-(piperazin-1-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;6-(4-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(1-(4-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperidin-1-yl)phenyl)amino)-2-(2-methylpiperidin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(5-((2-(2-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)aceticacid;1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylicacid;1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylicacid;4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;1-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylicacid;6-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylicacid;1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylicacid;1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-3-carbonitrile;2-(1-(4-((2-(3-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)aceticacid;1-(4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-3-carbonitrile;1-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylicacid;4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-2-cycloheptylpyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)aceticacid;4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-2-cycloheptylpyrimido[4,5-d]pyridazin-5(6H)-one;1-(4-((2-(4-cyanopiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylicacid;1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-carbonitrile;1-(4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-carbonitrile;1-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylicacid;2-(1-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylicacid;1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylicacid;2-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-1-yl)acetonitrile;2-(1-(4-((2-(4-(cyanomethyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)aceticacid;2-(4-(4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-1-yl)acetonitrile;6-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylicacid;1-(4-((2-(1,4-diazepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylicacid;6-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylicacid;1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylicacid;3-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-1-yl)-3-oxopropanenitrile;2-(1-(4-((2-(4-(2-cyanoacetyl)piperazin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)aceticacid;4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-2-(4-(2-isocyanoacetyl)piperazin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;6-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidine-4-carboxylicacid;1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidine-4-carboxylicacid;3-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-1-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-1-yl)-3-oxopropanenitrile;2-(1-(4-((2-(1-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)aceticacid;4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)methyl)phenyl)amino)-2-(1-(2-isocyanoacetyl)piperidin-4-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(4-(5-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperazin-1-yl)aceticacid;2-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-1,4-diazepan-1-yl)aceticacid;2-(1-(4-((4-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;3-(1-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)propanoicacid;6-(5-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)-6-azaspiro[2.5]octane-1-carboxylicacid;1-(5-oxo-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidine-4-carbonitrile;2-(1-(5-oxo-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(2-(4-ethylpiperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-phenyl-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)-2-(piperidin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(4-(4-((5-oxo-2-(piperidin-1-yl)-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-1,4-diazepan-1-yl)aceticacid;6-(4-((2-(4-methylpiperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(4-methylpiperidin-1-yl)-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;2-(azepan-1-yl)-4-((4-(2-(3-oxopiperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;6-(2-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)ethyl)-6-azaspiro[2.5]octane-1-carboxylicacid;2-(azepan-1-yl)-4-((4-(2-(diethylamino)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(cyclohexyl(methyl)amino)-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((2-(cyclohexyl(methyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)aceticacid;2-(4-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)aceticacid;2-(1-(4-((2-(3-methoxyphenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitrile;4-((4-(2-(1,4-diazepan-1-yl)ethoxy)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(3-oxopiperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(3-methoxyphenyl)-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(2-(dimethylamino)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(2-(piperidin-4-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(5-oxo-4-((4-(2-(piperidin-4-yl)ethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;6-(4-((2-(cyclohexyl(methyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylicacid;4-((4-(2-(1,4-diazepan-1-yl)ethoxy)phenyl)amino)-2-(piperidin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(2-(4-hydroxypiperidin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(3-(piperazin-1-yl)propyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(5-oxo-4-((4-(3-(piperazin-1-yl)propyl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(4-ethyl-3-oxopiperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-morpholino-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(2,6-dimethylmorpholino)-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-ethyl-3-oxopiperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(3-(4-hydroxypiperidin-1-yl)propyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;4-((6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)amino)-2-(piperidin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;4-((4-(2-(4-hydroxypiperidin-1-yl)ethoxy)phenyl)amino)-2-(piperidin-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(2-(4-hydroxy-4-methylpiperidin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(2-(4-hydroxy-4-methylpiperidin-1-yl)ethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(2-(diisopropylamino)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(5-oxo-4-((4-(piperazin-1-yl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(4-(3-hydroxypropyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-(2-hydroxyethyl)piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(4-((4-(2-(4-ethylpiperazin-1-yl)ethyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(2-(piperazin-1-yl)ethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;4-((4-(2-aminoethoxy)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(2-aminoethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(2-(4-hydroxypiperidin-1-yl)ethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(2-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)piperidin-1-yl)ethyl)piperidin-4-yl)acetonitrile;2-(1-(4-((4-(4-(3-hydroxypropyl)piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)acetonitrile;2-(1-(4-((4-(4-(cyanomethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;3-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)propanoicacid;2-(azepan-1-yl)-4-((4-(2-(4-ethylpiperazin-1-yl)ethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(2-(4-hydroxy-4-methylpiperidin-1-yl)ethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(4-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)-2-methylpropanoicacid;2-(azepan-1-yl)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;3-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)-3-oxopropanenitrile;2-(1-(4-((4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((6-(4-hydroxypiperidin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;(phosphonooxy)methyl6-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octane-1-carboxylate;3-(4-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)propanoicacid;2-(azepan-1-yl)-4-((6-(piperazin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(2-(2-hydroxyethyl)-2H-tetrazol-5-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(4-((4-(2-(diethylamino)ethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(2-ethyl-2H-tetrazol-5-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(2-ethyl-2H-tetrazol-5-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;4-((4-(2H-tetrazol-5-yl)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(4-(5-oxo-4-((4-(2-(piperazin-1-yl)ethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-1-yl)acetonitrile;2-(1-(5-oxo-4-((6-(piperazin-1-yl)pyridin-3-yl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-3-yl)aceticacid;2-(1-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-3-yl)aceticacid;3-(4-(5-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperazin-1-yl)-3-oxopropanenitrile;2-(5-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-2H-tetrazol-2-yl)aceticacid;2-(azepan-1-yl)-4-((6-(4-(2-hydroxyethyl)piperidin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;3-(4-(5-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperazin-1-yl)-3-oxopropanenitrile;2-(azepan-1-yl)-4-((6-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;3-(4-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1-yl)-3-oxopropanenitrile;2-(5-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-2H-tetrazol-2-yl)aceticacid;2-(azepan-1-yl)-4-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;4-((4-(4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)phenyl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(2H-tetrazol-5-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(4-((4-(4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(5-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-3-yl)aceticacid;2-(1-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-3-yl)aceticacid;2-(1-(4-((6-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1-yl)pyridin-3-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;4-((6-(4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)pyridin-3-yl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((6-(4-((2H-tetrazol-5-yl)methyl)piperidin-1-yl)pyridin-3-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(4-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)piperidin-1-yl)aceticacid;2-(azepan-1-yl)-4-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(4-((4-(4-(2-aminoethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(1-(hydroxymethyl)-6-azaspiro[2.5]octan-6-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(1-(hydroxymethyl)-6-azaspiro[2.5]octan-6-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(4-(3-hydroxypropyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-(3-hydroxypropyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(4-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)piperidin-1-yl)aceticacid;2-(azepan-1-yl)-4-((4-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(4-(1-hydroxy-2-methylpropan-2-yl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-(1-hydroxy-2-methylpropan-2-yl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(2-(4-ethylpiperazin-1-yl)-2-oxoethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(2-(4-ethylpiperazin-1-yl)-2-oxoethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(4-((4-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(3-(2-hydroxyethyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(4-(2,3-dihydroxypropyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-(2,3-dihydroxypropyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((6-(3-hydroxypiperidin-1-yl)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((6-(3-hydroxypiperidin-1-yl)pyridin-3-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(4,4-difluoropiperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4,4-difluoropiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(3-hydroxypiperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(3-hydroxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(2-(4-methylpiperazin-1-yl)-2-oxoethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(3-(hydroxymethyl)piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(3-(hydroxymethyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(3-(2-hydroxyethyl)piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(4-((4-(4-methoxypiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(4-methoxypiperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(4-fluoropiperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-fluoropiperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(4-((4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(piperidin-4-yloxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-onehydrochloride;2-(1-(4-((4-(2-hydroxyethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(2-hydroxyethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(3-hydroxypropoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(3-hydroxypropoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-(1-hydroxy-2-methylpropan-2-yl)-1,4-diazepan-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(4-(2-fluoroethyl)piperidin-1-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(4-(2-fluoroethyl)piperidin-1-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(4-((3,5-dimethoxyphenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(5-oxo-4-((4-(trifluoromethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((3,5-dimethoxyphenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-(trifluoromethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;3-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)propanoicacid;3-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)propanoicacid;2-(azepan-1-yl)-4-((4-(bis(2-hydroxyethyl)amino)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(bis(2-hydroxyethyl)amino)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(3-hydroxypropyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(3-hydroxypropyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((3-(hydroxymethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((3-(hydroxymethyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(4-((4-fluorophenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-fluorophenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(azepan-1-yl)-4-((4-((1-hydroxy-2-methylpropan-2-yl)oxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-((1-hydroxy-2-methylpropan-2-yl)oxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(4-((2-(azepan-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)-2-methylpropanoicacid;2-(4-((2-(4-(cyanomethyl)piperidin-1-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)-2-methylpropanoicacid;2-(azepan-1-yl)-4-((3,4-dimethoxyphenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((3,4-dimethoxyphenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((3-methoxyphenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((3-methoxyphenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(2-hydroxyethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(2-hydroxyethyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(2-methoxyethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(2-methoxyethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(5-oxo-4-((3,4,5-trimethoxyphenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-(benzo[d][1,3]dioxol-5-ylamino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-(benzo[d][1,3]dioxol-5-ylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-((1-(2-hydroxyethyl)piperidin-4-yl)oxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;sodium(2-(4-(cyanomethyl)piperidin-1-yl)-4-((4-(4-hydroxypiperidin-1-yl)phenyl)amino)-5-oxopyrimido[4,5-d]pyridazin-6(5H)-yl)methylphosphate;2-(azepan-1-yl)-4-((4-(hydroxymethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((4-(hydroxymethyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(4-((4-(methylsulfonyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(azepan-1-yl)-4-((4-(methylsulfonyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-one;2-(1-(4-((1H-benzo[d][1,2,3]triazol-5-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(5-oxo-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(4-((4-(3-fluoropropyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;2-(1-(4-((4-(difluoromethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitrile;or4-((1H-benzo[d][1,2,3]triazol-5-yl)amino)-2-(azepan-1-yl)pyrimido[4,5-d]pyridazin-5(6H)-one.23. The pharmaceutical composition of claim 1, wherein the one or moreexcipients are selected from the group consisting of adjuvants,antioxidants, binders, buffers, coatings, coloring agents, compressionaids, diluents, disintegrants, emulsifiers, emollients, encapsulatingmaterials, fillers, flavoring agents, glidants, granulating agents,lubricants, metal chelators, osmo-regulators, pH adjustors,preservatives, solubilizers, sorbents, stabilizing agents, sweeteners,surfactants, suspending agents, thickening agents, penetrationenhancers, and viscosity regulators.
 24. The pharmaceutical compositionof claim 1, wherein the one or more excipients comprise a pH adjustor.25. The pharmaceutical composition of claim 1, wherein the one or moreexcipients comprise a coating.
 26. The pharmaceutical composition ofclaim 1, wherein the composition is formulated for administration to apatient by a modified-release delivery device.
 27. The pharmaceuticalcomposition of claim 26, wherein the composition is formulated forextended release to the patient.
 28. The pharmaceutical composition ofclaim 26, wherein the composition is formulated for immediate release tothe patient.
 29. The pharmaceutical composition of claim 23, wherein theemulsifiers comprise polyoxyethylene fatty acid esters.
 30. Thepharmaceutical composition of claim 23, wherein the pH adjustorscomprise sodium hydroxide.
 31. The pharmaceutical composition of claim23, wherein the sweeteners comprise one or more of saccharin and syrups.32. The pharmaceutical composition of claim 23, wherein the thickeningagents comprise one or more of carboxypolymethylene andhydroxypropylmethylcellulose.
 33. The pharmaceutical composition ofclaim 23, wherein the penetration enhancers comprise one or more ofhydroxypolyethoxydodecane, DMSO, DMAC and DDM.